IL282840B1 - Substituted amide heterocyclic compounds for the treatment of conditions involving the regulation of IL-12, IL-23 AND/OR IFN-ALPHA - Google Patents

Substituted amide heterocyclic compounds for the treatment of conditions involving the regulation of IL-12, IL-23 AND/OR IFN-ALPHA

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IL282840B1
IL282840B1 IL282840A IL28284021A IL282840B1 IL 282840 B1 IL282840 B1 IL 282840B1 IL 282840 A IL282840 A IL 282840A IL 28284021 A IL28284021 A IL 28284021A IL 282840 B1 IL282840 B1 IL 282840B1
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acn
mmol
amino
pct
substituted
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IL282840A
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IL282840B2 (en
IL282840A (en
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Steven H Spergel
William J Pitts
Michael E Mertzman
Ryan M Moslin
Trevor C Sherwood
John L Gilmore
Alaric J Dyckman
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Bristol Myers Squibb Co
Steven H Spergel
William J Pitts
Michael E Mertzman
Ryan M Moslin
Trevor C Sherwood
John L Gilmore
Alaric J Dyckman
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Application filed by Bristol Myers Squibb Co, Steven H Spergel, William J Pitts, Michael E Mertzman, Ryan M Moslin, Trevor C Sherwood, John L Gilmore, Alaric J Dyckman filed Critical Bristol Myers Squibb Co
Publication of IL282840A publication Critical patent/IL282840A/en
Publication of IL282840B1 publication Critical patent/IL282840B1/en
Publication of IL282840B2 publication Critical patent/IL282840B2/en

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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Description

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date 07 May 2020 (07.05.2020) WIPO I PCT IlllllIllllIllllll/llIIIIIIIIIIIIIIIlIlIIIlIlIlIIlIIlIlIIII/IIII (10) International Publication Number WO 2020/092196 Al International Patent Classification: (51) C07D 401/12 (2006.01) C07D 401/14 (2006.01) C07D 403/12 (2006.01) C07D 403/14 (2006.01) C07D 413/12 (2006.01) C07D 413/14 (2006.01) C07D 417/12 (2006.01) C077) 477/74 (2006.01) C07D 487/04 (2006.01) A61K 31/501 (2006.01) A67P29/00 (2006.01) A67P37/00 (2006.01) (21) International Application Number: PCT/US2019/058268 w o 2020/092196 Al lllllllllllllllllllllllllllllllllllllllllllllllllllllll^ (22) International Filing Date: October 2019 (28.10.2019) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/752,414 30 October2018 (30.10.2018) US (71) Applicant: BRISTOL-MYERS SQUIBB COMPANY [US/US]; Route 206 and Province Line Road, Princeton, New Jersey 08543 (US). (72) Inventors: SPERGEL, Steven H.; c/0Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543 (US). PITTS, William J.;c/ 0Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543 (US). MERTZ- MAN, Michael E.;c/0 Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, New Jer ­sey 08543 (US). MOSLIN, Ryan M.;c/0 Bristol-My ­ers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543 (US). SHERWOOD, Trevor C.;c/0 Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543 (US). GILMORE, John L.;c/0 Bristol-Myers Squibb Compa­ny, Route 206 and Province Line Road, Princeton, New Jer ­sey 08543 (US). DYCKMAN, Alaric J.;c/0 Bristol-My ­ers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543 (US). (74) Agent: KORSEN, Elliottet al.; Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543 (US). (81) Designated States(unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States(unless otherwise indicated, for every kind of regional protection available) ׳ . ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — as to applicant's entitlement to apply for and be granted a patent (Rule 4.17(H))— as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(iii))— of inventorship (Rule 4.17 (iv)) Published: — with international search report (Art. 21(3)) (54) Title:AMIDE-SUBSTITUTED HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF CONDITIONS RELATED TO THE MODULATION OF IL-12, IL-23 AND/OR IFN-ALPHA (57) Abstract:Compounds having the following formula I: or a stereoisomer or pharmaceutically-acceptable salt thereof, where R1,3 4 5R , R , R , and R are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNa, by acting on Tyk-2 to cause signal transduction inhibition.
WO 2020/092196 PCT/US2019/058268 AMIDE-SUBSTITUTED HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF CONDITIONS RELATED TO THE MODULATION OF IL-12, IL-23 AND/OR IFN-ALPHA FIELD OF THE INVENTIONThis invention relates to compounds useful in the modulation of IL-12, IL-and/or IFNa by acting on Tyk-2 to cause signal transduction inhibition. Provided herein are amide-substituted heterocyclic compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to the modulation of IL-12, IL-23 and/or IFNa in a mammal.
BACKGROUND OF THE INVENTIONThe heterodimeric cytokines interleukin (IL)-12 and IL-23, which share a common p40 subunit, are produced by activated antigen-presenting cells and are critical in the differentiation and proliferation of Thl and Thl7 cells, two effector T cell lineages which play key roles in autoimmunity. IL-23 is composed of the p40 subunit along with a unique pl9 subunit. IL-23, acting through a heterodimeric receptor composed of IL- 23R and IL-12RP1, is essential for the survival and expansion of Thl? cells which produce pro-inflammatory cytokines such as IL-17A, IL-17F, IL-6 and TNF-a (McGeachy, M.J. et al., "The link between IL-23 and Thl7 cell-mediated immune pathologies", Semin. Immunol.. 19:372-376 (2007)). These cytokines are critical in mediating the pathobiology of a number of autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus. IL-12, in addition to the p40 subunit in common with IL-23, contains a p35 subunit and acts through a heterodimeric receptor composed of IL-12RP1 and IL-12RP2. IL-12 is essential for Thl cell development and secretion of IFNy, a cytokine which plays a critical role in immunity by stimulating MHC expression, class switching of B cells to IgG subclasses, WO 2020/092196 PCT/US2019/058268 and the activation of macrophages (Gracie, J.A. et al., "Interleukin- 12 induces interferon- gamma-dependent switching of IgG alloantibody subclass", Eur. J. Immunol., 26:1217­1221 (1996); Schroder, K. et al., "Interferon-gamma: an overview of signals, mechanisms and functions", J. Leukoc. Biol., 75(2): 163-189 (2004)).The importance of the p40-containing cytokines in autoimmunity is demonstrated by the discovery that mice deficient in either p40, pl9, or IL-23R are protected from disease in models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus and psoriasis, among others (Kyttaris, V.C. et al., "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice", J. Immunol., 184:4605-4609 (2010); Hong, K. et al., "IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis like skin disorder", J. Immunol., 162:7480-7491 (1999); Hue, S. et al., "Interleukin-23 drives innate and T cell- mediated intestinal inflammation", J. Exp. Med., 203:2473-2483 (2006); Cua, D.J. et al., "Interleukin-23 rather than interleukin- 12 is the critical cytokine for autoimmune inflammation of the brain", Nature, 421:744-748 (2003); Murphy, C.A. et al., "Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation", J. Exp. Med., 198:1951-1957 (2003)).In human disease, high expression of p40 and pl9 has been measured in psoriatic lesions, and Th 17 cells have been identified in active lesions in the brain from MS patients and in the gut mucosa of patients with active Crohn's disease (Lee, E. et al., "Increased expression of interleukin 23 pl9 and p40 in lesional skin of patients with psoriasis vulgaris", J. Exp. Med., 199:125-130 (2004); Tzartos, IS. et al., "Interleukin- production in central nervous system infiltrating T cells and glial cells is associated with active disease in multiple sclerosis", Am. J. Pathol., 172:146-155 (2008)). The mRNA levels of pl9, p40, and p35 in active SLE patients were also shown to be significantly higher compared with those in inactive SLE patients (Huang, X. et al., "Dysregulated expression of interleukin-23 and interleukin- 12 subunits in systemic lupus erythematosus patients". Mod. Rheumatol., 17:220-223 (2007)), and T cells from lupus patients have a predominant Thl phenotype (Tucci, M. et al., "Overexpression of interleukin- 12 and T helper 1 predominance in lupus nephritis", Clin. Exp. Immunol. , 154:247-254 (2008)).Moreover, genome-wide association studies have identified a number of loci associated with chronic inflammatory and autoimmune diseases that encode factors that WO 2020/092196 PCT/US2019/058268 function in the IL-23 and IL-12 pathways. These genes include IL23A, IL12A, IL12B, IL12RB1, IL12RB2, IL23R, JAK2, TYK2, STAT3, and STAT4 (Lees, C.W. et al., "New IBD genetics: common pathways with other diseases", Gut, 60:1739-1753 (2011); Tao, J.H. et al., "Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases", Mol. Biol. Rep., 38:4663-4672 (2011); Cho, J.H. et al., "Recent insights into the genetics of inflammatory bowel disease", Gastroenterology, 140:1704-1712 (2011)).Indeed, anti-p40 treatment, which inhibits both IL-12 and IL-23, as well as IL-23- specific anti-pl 9 therapies have been shown to be efficacious in the treatment of autoimmunity in diseases including psoriasis, Crohn's Disease and psoriatic arthritis (Leonardi, C.L. et al., "PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin- 12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1)", Lancet, 371:1665-1674 (2008); Sandborn, W.J. et al., "Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin- 12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease", Gastroenterology, 135:1130-1141 (2008); Gottlieb, A. et al., "Ustekinumab, a human interleukin 12/monoclonal antibody, for psoriatic arthritis: randomized, double-blind, placebo- controlled, crossover trial", Lancet, 373:633-640 (2009)). Therefore, agents which inhibit the action of IL-12 and IL-23 may be expected to have therapeutic benefit in human autoimmune disorders.The Type I group of interferons (IFNs), which include the IFNa members as well as IFN, IFNs, IFNk and IFNO, act through a heterodimer IFNa/ receptor (IFNAR). Type I IFNs have multiple effects in both the innate and adaptive immune systems including activation of both the cellular and humoral immune responses as well as enhancing the expression and release of autoantigens (Hall, J.C. et al., "Type I interferons: crucial participants in disease amplification in autoimmunity", Nat. Rev. Rheumatol, 6:40-49 (2010)).In patients with systemic lupus erythematosus (SLE), a potentially fatal autoimmune disease, increased serum levels of interferon (IFN)a (a type I interferon) or increased expression of type I IFN-regulated genes (a so-called IFNa signature) in peripheral blood mononuclear cells and in affected organs has been demonstrated in a WO 2020/092196 PCT/US2019/058268 majority of patients (Bennett, L. et al., "Interferon and granulopoiesis signatures in systemic lupus erythematosus blood", J. Exp. Med., 197:711-723 (2003); Peterson, K.S. et al., "Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli", J. Clin. Invest., 113:1722-17(2004)), and several studies have shown that serum IFNa levels correlate with both disease activity and severity (Bengtsson, A.A. et al., "Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies", Lupus, 9:664-671 (2000)). A direct role for IFNa in the pathobiology of lupus is evidenced by the observation that the administration of IFNa to patients with malignant or viral diseases can induce a lupus-like syndrome. Moreover, the deletion of the IFNAR in lupus-prone mice provides high protection from autoimmunity, disease severity and mortality (Santiago-Raber, ML. et al., "Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice", J. Exp. Med, 197:777-788 (2003)), and genome-wide association studies have identified loci associated with lupus that encode factors that function in the type I interferon pathway, including IRF5, IKBKE, TYK2, and STAT4 (Deng, Y. et al., "Genetic susceptibility to systemic lupus erythematosus in the genomic era", Nat. Rev. Rheumatol., 6:683-692 (2010);Sandling, J.K. et al., "A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SEE", Eur. J. Hum. Genet., 19:479-484 (2011)). In addition to lupus, there is evidence that aberrant activation of type I interferon-mediated pathways are important in the pathobiology of other autoimmune diseases such as Sjogren's syndrome and scleroderma (Bave, U. et al., "Activation of the type I interferon system in primary Sjogren's syndrome: a possible etiopathogenic mechanism", Arthritis Rheum., 52:1185-1195 (2005); Kim, D. et al., "Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis", Arthritis Rheum., 58:2163-2173 (2008)). Therefore, agents which inhibit the action of type I interferon responses may be expected to have therapeutic benefit in human autoimmune disorders.Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of nonreceptor tyrosine kinases and has been shown to be critical in regulating the signal transduction cascade downstream of receptors for IL-12, IL-23 and type I interferons in both mice (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12/Thl WO 2020/092196 PCT/US2019/058268 and IL-23/Thl7 Axes In vivo ", J. Immunol., 187:181-189 (2011); Prchal-Murphy, M. et al., "TYK2 kinase activity is required for functional type I interferon responses in vivo ", PLoS One, 7:e39141 (2012)) and humans (Minegishi, Y. et al., "Human tyrosine kinase deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity", Immunity, 25:745-755 (2006)). Tyk2 mediates the receptor-induced phosphorylation of members of the STAT family of transcription factors, an essential signal that leads to the dimerization of STAT proteins and the transcription of STAT- dependent pro-inflammatory genes. Tyk2-def1cient mice are resistant to experimental models of colitis, psoriasis and multiple sclerosis, demonstrating the importance of Tyk2- mediated signaling in autoimmunity and related disorders (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12/Thl and IL-23/Thl7 Axes In vivo ", J. Immunol., 187:181-189 (2011); Oyamada, A. et al., "Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis", J. Immunol., 183:7539-7546 (2009)).In humans, individuals expressing an inactive variant of Tyk2 are protected from multiple sclerosis and possibly other autoimmune disorders (Couturier, N. et al., "Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility", Brain, 134:693-703 (2011)). Genome-wide association studies have shown other variants of Tyk2 to be associated with autoimmune disorders such as Crohn's Disease, psoriasis, systemic lupus erythematosus, and rheumatoid arthritis, further demonstrating the importance of Tyk2 in autoimmunity (Ellinghaus, D. et al., "Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci", Am. J. Hum. Genet., 90:636-647 (2012); Graham, D. et al., "Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families", Rheumatology (Oxford), 46:927-930 (2007); Eyre, S. et al., "High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis", Nat. Genet., 44:1336-1340 (2012)).In view of the conditions that may benefit by treatment involving the modulation of cytokines and/or interferons, new compounds capable of modulating cytokines and/or interferons, such as IL-12, IL-23 and/or IFNa, and methods of using these compounds may provide substantial therapeutic benefits to a wide variety of patients in need thereof.
WO 2020/092196 PCT/US2019/058268 SUMMARY OF THE INVENTIONThe invention is directed to compounds of Formula I, infra, that which are useful as modulators of IL-12, IL-23 and/or IFNaby inhibiting Tyk2-mediated signal transduction.The present invention also provides processes and intermediates for making the compounds of the present invention.The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention.The present invention also provides a method for the modulation of IL-12, IL-and/or IFNa by inhibiting Tyk-2-mediated signal transduction comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention.The present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention.A preferred embodiment is a method for treating inflammatory and autoimmune diseases or diseases. For the purposes of this invention, an inflammatory and autoimmune disease or disorder includes any disease having an inflammatory or autoimmune component.The present invention also provides the use of the compounds of the present invention for the manufacture of a medicament for the treatment of cancers.The present invention also provides the compounds of the present invention for use in therapy.These and other features of the invention will be set forth in the expanded form as the disclosure continues.
DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTIONIn a first aspect of the present invention, there is provided a compound of formula (I) WO 2020/092196 PCT/US2019/058268 I whereinX is N or CH;R1 is H, CD3, C1-3 alkyl or C3-6 cycloalkyl;R2 is H, -C(O)R2a; C1-6 alkyl, -(CH2)r -3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle substituted with 0-4 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR n Rn , -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R3 is H, C1-3 alkyl or C3-6 cycloalkyl;R4 is H, C1-3 alkyl or C3-6 cycloalkyl;R5 is Cm alkyl substituted with 0-1 R5a, Cm alkoxy substituted with 0-1 R5a, (CH2)r -phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle ;R5a is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-3 alkyl or (CH2)r -phenyl;R6 is a -(CH2)-5-7 membered heterocycle substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNR11R11, -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl; WO 2020/092196 PCT/US2019/058268 R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r-phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In a second aspect of the present invention, there is provided a compound of the R6 formula WO 2020/092196 PCT/US2019/058268 I whereinX is N or CH;R1 is H, CD3, C1-3 alkyl or C3-6 cycloalkyl;R2 is H, -C(O)R2a; C1-6 alkyl, -(CH2)r -3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle substituted with 0-4 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR n Rn , -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R3 is H, C1-3 alkyl or C3-6 cycloalkyl;R4 is H or C1-3 alkyl;R5 is Cm alkyl substituted with 0-1 R5a, Cm alkoxy substituted with 0-1 R5a, (CH2)r -phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle ;R5a is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-3 alkyl or (CH2)r -phenyl;R6 is a -(CH2)-5-7 membered heterocycle substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNR11R11, -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, Cm alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rOR b, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb WO 2020/092196 PCT/US2019/058268 C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r -phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r -phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In a third aspect of the present invention, there is provided a compound of the formula I whereinX is N or CH;R1 is H, CD3, C1-3 alkyl or C3.6 cycloalkyl; WO 2020/092196 PCT/US2019/058268 R2 is H, -C(O)R2a; C1-6 alkyl, -(CH2)r -3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle substituted with 0-4 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)r NR11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R3 is H, C1-3 alkyl or C3-6 cycloalkyl;R4 is H or C1-3 alkyl;R5 is C1-4 alkyl or C1-4 alkoxy;R5a is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-3 alkyl or (CH2)r -phenyl;R6 is a -(CH2)-5-7 membered heterocycle substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNR11R11, -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rOR b, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf; WO 2020/092196 PCT/US2019/058268 Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r -phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r -phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 4th aspect of the present invention, there is provided a compound of the formula whereinX is N or CH;R2 is H, -C(O)R2a; C1-6 alkyl, -(CH2)r -3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle substituted with 0-4 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , WO 2020/092196 PCT/US2019/058268 -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R3 is H, C1-3 alkyl or C3-6 cycloalkyl;R4 is H or C1-3 alkyl;R5 is C1-4 alkyl or C1-4 alkoxy,R5a is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-3 alkyl or (CH2)r -phenyl;R6 is a -(CH2)-5-7 membered heterocycle substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rOR b, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r-phenyl substituted with 0-3 Rf; WO 2020/092196 PCT/US2019/058268 Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r -phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In a Sth aspect of the present invention, there is provided a compound of the formula whereinX is N or CH;R2 is H, -C(O)R2a; C1-6 alkyl, -(CH2)r -3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle substituted with 0-4 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S^pNR1^11, -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R4 is H or C1-3 alkyl;R5 is C1-4 alkyl or C1-4 alkoxy, WO 2020/092196 PCT/US2019/058268 R5a is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-3 alkyl or (CH2)r -phenyl;R6 is a -(CH2)-5-7 membered heterocycle substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rOR b, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r-phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2; WO 2020/092196 PCT/US2019/058268 r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 6th aspect of the present invention, there is provided a compound of the formula whereinX is N or CH;R2 is H, -C(O)R2a; C1-6 alkyl, -(CH2)r -3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle substituted with 0-4 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R4 is H or C1-3 alkyl;R6 is a -(CH2)-5-7 membered heterocycle substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl; WO 2020/092196 PCT/US2019/058268 R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r-phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 7th aspect of the present invention, there is provided a compound of the formula WO 2020/092196 PCT/US2019/058268 whereinX is N or CH;R2 is H, -C(O)R2a; C1-6 alkyl, -(CH2)r -3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle substituted with 0-4 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR n Rn , -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R4 is H or C1-3 alkyl;R6 is a triazole, oxadiazole, thiazole, oxazole or pyrazole substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rOR b, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd ; WO 2020/092196 PCT/US2019/058268 Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r -phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In an Sth aspect of the present invention, there is provided a compound of the formula whereinX is N or CH;R2 is H, -C(O)-cyclopropyl, -C(O)-CH2-cyclopropyl, pyridine, pyridazine, pyrazole, triazole or piperazine, all of which, except the H group, may be substituted with 0-3 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNR11R11, -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra; WO 2020/092196 PCT/US2019/058268 R4 is H or C1-3 alkyl;R6 is a triazole, oxadiazole, thiazole, oxazole or pyrazole substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)r NR11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rOR b, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r-phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5; WO 2020/092196 PCT/US2019/058268 or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 9th aspect of the present invention, there is provided a compound of the formula R6 R3 whereinR1 is H, CD3, C1-3 alkyl or C3-6 cycloalkyl;R2 is H, -C(O)R2a; C1-6 alkyl, -(CH2)r -3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle substituted with 0-4 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)r NR11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R3 is H, C1-3 alkyl or C3-6 cycloalkyl;R4 is H, C1-3 alkyl or C3-6 cycloalkyl;R5 is Cm alkyl substituted with 0-1 R5a, Cm alkoxy substituted with 0-1 R5a, (CH2)r -phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle ;R5a is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-3 alkyl or (CH2)r -phenyl;R6 is a -(CH2)-5-7 membered heterocycle substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , WO 2020/092196 PCT/US2019/058268 -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r-phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 10th aspect of the present invention, there is provided a compound of the formula WO 2020/092196 PCT/US2019/058268 R6 whereinR2 is H, -C(O)-cyclopropyl, -C(O)-CH2-cyclopropyl, pyridine, pyridazine, pyrazole, triazole or piperazine, all of which, except the H group, may be substituted with 0-3 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)r NR11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R4 is H or C1-3 alkyl;R6 is a triazole, oxadiazole, thiazole, oxazole or pyrazole substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rOR b, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb WO 2020/092196 PCT/US2019/058268 C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r -phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r -phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In an 11th aspect of the present invention, there is provided a compound of the formula whereinR1 is H, CD3, C1-3 alkyl or C3.6 cycloalkyl; WO 2020/092196 PCT/US2019/058268 R2 is H, -C(O)R2a; C1-6 alkyl, -(CH2)r -3-14 membered carbocycle substituted with 0-1 R2a or a 5-12 membered heterocycle substituted with 0-4 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)r NR11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R3 is H, C1-3 alkyl or C3-6 cycloalkyl;R4 is H, C1-3 alkyl or C3-6 cycloalkyl;R5 is Cm alkyl substituted with 0-1 R5a, Cm alkoxy substituted with 0-1 R5a, (CH2)r -phenyl substituted with 0-3 R5a or a -(CH2)-5-7 membered heterocycle ;R5a is is independently at each occurrence, H, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-3 alkyl or (CH2)r -phenyl;R6 is a -(CH2)-5-7 membered heterocycle substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNR11R11, -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, Cm alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rOR b, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf; WO 2020/092196 PCT/US2019/058268 Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r -phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r -phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf;Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C!-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In a 12th aspect of the present invention, there is provided a compound of the formula whereinR2 is H, -C(O)-cyclopropyl, -C(O)-CH2-cyclopropyl, pyridine, pyridazine, pyrazole, triazole or piperazine, all of which, except the H group, may be substituted with 0-3 R2a;R2a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)rNR 11R11, WO 2020/092196 PCT/US2019/058268 -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R4 is H or C1-3 alkyl;R6 is a triazole, oxadiazole, thiazole, oxazole or pyrazole substituted with 0-3 R6a;R6a is independently at each occurrence, H, OCF3, CN, NO2, -(CH2)r ORb, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, CH2)r NR11R11, -(CH2)rC(O)NR 11R11, -(CH2)rNR bC(O)Rc, -(CH2)r NRbC(O)ORc, -NRbC(O)NRn Rn , -S(O)pNRn Rn , -NRbS(O)pRc, -S(O)PRC, C1-6 alkyl substituted with 0-3 Ra, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Ra, -(CH2)r -3-14 membered carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle substituted with 0-2 Ra;R7 is H, halogen or C1-3 alkyl;R11 at each occurrence is independently H, C1-4 alkyl substituted with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r -phenyl substituted with 0-3 Rd or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rd ;Ra at each occurrence is independently H, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, -(CH2)rOR b, -(CH2)rSR b, -(CH2)rC(O)R b, -(CH2)rC(O)OR b, -(CH2)rOC(O)R b, -(CH2)rNR 11R11, -(CH2)rC(O)NR n Rn , -(CH2)r NRbC(O)Rc, -(CH2)r NRb C(O)ORC, -NRbC(O)NRn Rn , -S(O)PNR11R11, -NRbS(O)pRc, -S(O)RC, -S(O)2RC, C1-alkyl substituted with 0-3 Rf, C1-6 haloalkyl, -(CH2)r -3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle substituted with 0-3 Rf;Rb is H, C1-6 alkyl substituted with 0-3 Rd , C1-6 haloalkyl, C3-6 cycloalkyl substituted with 0-2 Rd , or -(CH2)r -5-7 membered heterocycle substituted with 0-3 Rf or (CH2)r-phenyl substituted with 0-3 Rd ;Rc is C1-6 alkyl substituted with 0-3 Rf, (CH2)r -C3-6 cycloalkyl substituted with 0-Rf or (CH2)r-phenyl substituted with 0-3 Rf;Rd is independently at each occurrence, hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -ORe, -(CH2)rC(O)R c, -NReRe, -NReC(O)ORc, C1-6 alkyl or (CH2)r-phenyl substituted with 0-3 Rf;Re is independently at each occurrence, hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)r-phenyl substituted with 0-3 Rf; WO 2020/092196 PCT/US2019/058268 Rf is independently at each occurrence, hydrogen, halo, CN, NH2, OH, C3-cycloalkyl, CF3, O(C1-6 alkyl) or a -(CH2)r-5-7 membered heterocycle ;p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5;or a stereoisomer or pharmaceutically acceptable salt thereof.
In another aspect, there is provided a compound selected from the exemplified examples within the scope of the first aspect, or a pharmaceutically acceptable salt or stereoisomer thereof.In another aspect, there is provided a compound selected from any subset list of compounds within the scope of any of the above aspects.In another aspect, there is provided a compound (IUPAC naming convention) selected from6-cyclopropaneamido-4- {[2-methoxy-3 -(5 - {1 -[(2- methoxyethyl)carbamoyl]propyl}-l,2,4-oxadiazol-3-yl)phenyl]amino}-N- (2H3)methylpyridazine-3-carboxamide,6-cyclopropaneamido-4-[(2-methoxy-3-{5-[l-(morpholin-4-yl)-l-oxopentan-2- yl]-l,2,4-oxadiazol-3-yl}phenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,6-cyclopropaneamido-4-{[2-methoxy-3-(5-{l-[(2-methoxyethyl) carbamoyl]butyl}-l,2,4-oxadiazol-3-yl)phenyl]amino}-N-(2H3)methylpyridazine-3- carboxamide,tert-butyl N-[(lR,2R)-2-(tert-butoxy)-l-{5-[3-({6-cyclopropaneamido-3- [(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-l,2,4-oxadiazol-3- yl}propyl]carbamate,6-cyclopropaneamido-4-[(3-{3-[(lR,2R)-l-acetamido-2-hydroxypropyl]-l,2,4- oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,methyl N-[(lR,2R)-l-{5-[3-({6-cyclopropaneamido-3- [(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-l,2,4-oxadiazol-3-yl}- 2-hydroxypropyl]carbamate,6-cyclopropaneamido-4-[(3-{3-[(lR,2R)-2-hydroxy-l-propanamidopropyl]-l,2,4- oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide, WO 2020/092196 PCT/US2019/058268 tert-butyl N-[(lR)-2-(tert-butoxy)-l-{5-[3-({6-cyclopropaneamido-3- [(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-l,2,4-oxadiazol-3- yl}ethyl]carbamate,6-cyclopropaneamido-4-[(3-{3-[(lR)-2-hydroxy-l-propanamidoethyl]-l,2,4- oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,6-cyclopropaneamido-4-[(3-{3-[(lR)-l-acetamido-2-hydroxyethyl]-l,2,4- oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,(2R)-2-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4- yl}amino)-2-methoxyphenyl]-l,2,4-oxadiazol-3-yl}-2-acetamidoethyl acetate,6-cyclopropaneamido-4-[(3-{3-[(lR)-2-hydroxy-l-(2-methoxyacetamido)ethyl]- l,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3- carboxamide,6-cyclopropaneamido-4-[(3 - { 3 -[(1 S,2S)-1 -acetamido-2-hydroxypropyl]-1,2,4- oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,6-cyclopropaneamido-4- [(3 - { 3 -[(1 S,2 S)-2-hydroxy- 1 -(2-methoxyacetamido)propyl]-l,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N- (2H3)methylpyridazine-3-carboxamide,tert-butyl N-[(lS,2S)-2-(tert-butoxy)-l-{5-[3-({6-cyclopropaneamido-3- [(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-l,2,4-oxadiazol-3- yl}propyl]carbamate,6-cyclopropaneamido-4-[(3-{3-[(lS,2S)-2-hydroxy-l-propanamidopropyl]-l,2,4- oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,tert-butyl N-[(lS)-2-(tert-butoxy)-l-{5-[3-({6-cyclopropaneamido-3- [(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-l,2,4-oxadiazol-3- yl}ethyl]carbamate, or6-cyclopropaneamido-4-[(3-{3-[(lS)-l-acetamido-2-hydroxyethyl]-l,2,4- oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
In another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of formula I and a pharmaceutically acceptable carrier or diluent.
WO 2020/092196 PCT/US2019/058268 The present invention is also directed to pharmaceutical compositions useful in treating diseases associated with the modulation of IL-12, IL-23 and/or IFNa by acting on Tyk-2 to cause signal transduction inhibition, comprising compounds of formula I, or pharmaceutically-acceptable salts thereof, and pharmaceutically-acceptable carriers or diluents.The invention further relates to methods of treating diseases associated with the modulation of IL-12, IL-23, and/or IFNa, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to formula I.The present invention also provides processes and intermediates for making the compounds of the present invention.The present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention.The present invention also provides a method of treating an inflammatory or autoimmune disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases) comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I.The present invention also provides a method for treating a disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, Crohn's Disease, psoriatic arthritis, Sjogren's syndrome, systemic scleroderma, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult onset Stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes, insulin dependent diabetes mellitus, sepsis, septic shock, Shigellosis, pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), WO 2020/092196 PCT/US2019/058268 ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.The present invention also provides a method of treating an inflammatory or autoimmune disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of said diseases), comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the disease is selected from systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, Crohn's Disease, ulcerative colitis, type 1 diabetes, psoriasis, rheumatoid arthritis, systemic onset juvenile idiopathic arthritis, ankylosing spondylitis, and multiple sclerosis.The present invention also provides a method for treating rheumatoid arthritis or the use of the compounds of the present invention for the manufacture of a medicament for the treatment of rheumatoid arthritis, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I.In addition, the present invention also provides a method of treating a condition (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these conditions) comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of Formula I, wherein the condition is selected from acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, ocular neovasculization, and infantile haemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, Type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin diseases, Evans syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathies, pemphigus vulgaris and asthma.
WO 2020/092196 PCT/US2019/058268 The present invention also provides a method of treating an IL-12, IL-23, and/or IFNa mediated disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula I.The present invention also provides a method of treating an IL-12, IL-23 and/or IFNa mediated disease (or use of the compounds of the present invention for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula I, wherein the IL-12, IL-23 and/or IFNa mediated disease is a disease modulated by IL-12, IL-23 and/or IFNa.The present invention also provides a method of treating diseases, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound of formula I in combination with other therapeutic agents.The present invention also provides the compounds of the present invention for use in therapy.In another embodiment, compounds of formula I are selected from exemplified compounds or combinations of exemplified compounds or other embodiments herein.In another embodiment are compounds having an IC50 < 1000 nM in at least one of the assays described below.The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.
DETAILED DESCRIPTION OF THE INVENTION WO 2020/092196 PCT/US2019/058268 The following are definitions of terms used in this specification and appended claims. The initial definition provided for a group or term herein applies to that group or term throughout the specification and claims, individually or as part of another group, unless otherwise indicated.Compounds of this invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and /ra«5-geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.When any variable (e.g., R3) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R3, then said group may optionally be substituted with up to two R3 groups and R3 at each occurrence is selected independently from the definition of R3. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, all WO 2020/092196 PCT/US2019/058268 shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N—>0) derivative.
In accordance with a convention used in the art, is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom.The term "optionally substituted" in reference to a particular moiety of the compound of Formula I (e.g., an optionally substituted heteroaryl group) refers to a moiety having 0, 1, 2, or more substituents. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable.As used herein, the term "at least one chemical entity" is interchangeable with the term "a compound".As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-10 alkyl" (or alkylene), is intended to include Ci, C2, C3, C4, C5, C6, C7, C8, C9, and Cw alkyl groups. Additionally, for example, "C1-C6 alkyl" denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, /-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like."Alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon-carbon bonds that may occur in any stable point along the chain. For example, "C2-6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4- methyl-3-pentenyl, and the like.
WO 2020/092196 PCT/US2019/058268 "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain. For example, "C2-6 alkynyl" (or alkynylene), is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.One skilled in the field will understand that, when the designation "CO2" is used o herein, this is intended to refer to the group co—.When the term "alkyl" is used together with another group, such as in "arylalkyl", this conjunction defines with more specificity at least one of the substituents that the substituted alkyl will contain. For example, "arylalkyl" refers to a substituted alkyl group as defined above where at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl(C0-4)alkyl includes a substituted lower alkyl having at least one aryl substituent and also includes an aryl directly bonded to another group, i.e., aryl(Co)alkyl. The term "heteroarylalkyl" refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl.When reference is made to a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group, these groups are substituted with one to three substituents as defined above for substituted alkyl groups.The term "alkoxy" refers to an oxygen atom substituted by alkyl or substituted alkyl, as defined herein. For example, the term "alkoxy" includes the group -O-C1-6alkyl such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3- methylpentoxy, and the like. "Lower alkoxy" refers to alkoxy groups having one to four carbons.It should be understood that the selections for all groups, including for example, alkoxy, thioalkyl, and aminoalkyl, will be made by one skilled in the field to provide stable compounds.The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When a substituent is oxo, or keto, (z.e., =0) then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise specified, substituents are named into WO 2020/092196 PCT/US2019/058268 the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and subsequent formulation into an efficacious therapeutic agent. It is preferred that the presently recited compounds do not contain aN-halo, S(O)2H, or S(O)H group.The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or poly- cyclic ring systems. C3-7 cycloalkyl is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having to 12 carbon atoms in the ring portion, such as phenyl, and naphthyl groups, each of which may be substituted.
WO 2020/092196 PCT/US2019/058268 Accordingly, in compounds of formula I, the term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclooctyl, etc., as well as the following ring systems: The term "halo" or "halogen" refers to chloro, bromo, fluoro and iodo.The term "haloalkyl" means a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono, bi, and trifluoromethyl.The term "haloalkoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3.Thus, examples of aryl groups include: may be substituted at any available carbon or nitrogen atom. A preferred aryl group is optionally-substituted phenyl.
The terms "heterocycle", "heterocycloalkyl", "heterocyclo", "heterocyclic", or "heterocyclyl" may be used interchangeably and refer to substituted and unsubstituted 3- to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15- WO 2020/092196 PCT/US2019/058268 membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N), said heteroatom containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. As used herein the terms "heterocycle", "heterocycloalkyl", "heterocyclo", "heterocyclic", and "heterocyclyl" include "heteroaryl" groups, as defined below.In addition to the heteroaryl groups described below, exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro- 1,1-dioxothienyl and the like. Exemplary bicyclic heterocyclo groups include quinuclidinyl. Additional The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6- membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14- membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings, said heteroatom-containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring WO 2020/092196 PCT/US2019/058268 has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non- aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. As valence allows, if said further ring is cycloalkyl or heterocyclo it is additionally optionally substituted with =0 (oxo).Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.In compounds of formula I, preferred heteroaryl groups include: be substituted at any available carbon or nitrogen atom.
Unless otherwise indicated, when reference is made to a specifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl) or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, WO 2020/092196 PCT/US2019/058268 and furyl) the reference is intended to include rings having 0 to 3, preferably 0 to 2, substituents selected from those recited above for the aryl, cycloalkyl, heterocyclo and/or heteroaryl groups, as appropriate.The term "carbocyclyl" or "carbocyclic" refers to a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of mono- and bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, l-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl and naphthyl. The carbocyclic ring may be substituted in which case the substituents are selected from those recited above for cycloalkyl and aryl groups.The term "heteroatoms" shall include oxygen, sulfur and nitrogen.When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds and compounds useful as pharmaceutically-acceptable compounds and/or intermediate compounds useful in making pharmaceutically-acceptable compounds.The compounds of formula I may exist in a free form (with no ionization) or can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to the free form and to salts thereof. The term "salt(s)" denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, the term "salt(s)" may include zwitterions (inner salts), e.g., when a compound of formula I, contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the WO 2020/092196 PCT/US2019/058268 invention. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of the formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2- hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- P-phenethylamine, 1-ephenamine, 7V,7V'-dibenzyl ethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Preferred salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate salts.The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of WO 2020/092196 PCT/US2019/058268 sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.As used herein, "pharmaceutically-acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically-acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically-acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.The pharmaceutically-acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers may include compounds which are optical isomers through possession of one or more chiral atoms, as well as compounds which are optical isomers by virtue of limited rotation about one or more bonds (atropisomers). The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be WO 2020/092196 PCT/US2019/058268 resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include °C and 14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.Prodrugs and solvates of the inventive compounds are also contemplated. The term "prodrug" denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, and/or a salt and/or solvate thereof. Any compound that will be converted in vivo to provide the bioactive agent (z.e., the compound for formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include C1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6alkanoyloxy-C1-6alkyl, e.g., acetoxymethyl, pivaloyloxymethyl or propionyl oxymethyl, C1-6alkoxycarbonyloxy-C1-6alkyl, e.g., methoxycarbonyl-oxym ethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2- oxo-1,3-dioxolen-4-yl)-methyl and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.
WO 2020/092196 PCT/US2019/058268 Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985);b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and Development, pp. 113- 191, Harwood Academic Publishers (1991); andc) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992), each of which is incorporated herein by reference.
Compounds of the formula I and salts thereof may exist in their tautomeric form, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that the all tautomeric forms, insofar as they may exist, are included within the invention. Additionally, inventive compounds may have trans- and cz'5-isomers.It should further be understood that solvates (e.g., hydrates) of the compounds of Formula I are also with the scope of the present invention. Methods of solvation are generally known in the art.
UTILITYThe compounds of the invention modulate IL-23-stimulated and IFNa-stimulated cellular functions, including gene transcription. Other types of cellular functions that may be modulated by the compounds of the instant invention include, but are not limited to, IL-12-stimulated responses.Accordingly, compounds of formula I have utility in treating conditions associated with the modulation of the function of IL-23 or IFNa, and particularly the selective inhibition of function of IL-23, IL-12 and/or IFNa, by acting 0nTyk2 to mediate signal transduction. Such conditions include IL-23-, IL-12-, or IFNa-associated diseases in which pathogenic mechanisms are mediated by these cytokines.As used herein, the terms "treating" or "treatment" encompass the treatment of a disease state in a mammal, particularly in a human, and include: (a) preventing or delaying the occurrence of the disease state in a mammal, in particular, when such WO 2020/092196 PCT/US2019/058268 mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) inhibiting the disease state, i.e., arresting its development; and/or (c) achieving a full or partial reduction of the symptoms or disease state, and/or alleviating, ameliorating, lessening, or curing the disease or disorder and/or its symptoms.In view of their activity as modulators of IL-23-, IL-12 and IFNa-stimulated cellular responses, compounds of Formula I are useful in treating IL-23-, IL-12- or IFNa- associated diseases including, but not limited to, inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosis, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, psoriasis; auto-inflammatory diseases including CAPS, TRAPS, FMF, adult onset stills, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders such as acute myelogenous leukemia, chronic myelogenous leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; infectious diseases such as sepsis, septic shock, and Shigellosis; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury, oncologic and viral diseases such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS, respectively.More particularly, the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's WO 2020/092196 PCT/US2019/058268 syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic P-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; stroke, myocardial ischemia, ischemia in stroke heart attacks, organ hyposia [should this be hypoxia], vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase syndase-2, and pemphigus vulgaris. Preferred methods of treatment are those wherein the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris. Alternatively preferred methods of treatment are those wherein the condition is selected from ischemia reperfusion injury, including cerebral ischemia reperfusions injury arising from stroke and cardiac ischemia reperfusion injury arising from myocardial infarction. Another preferred method of treatment is one in which the condition is multiple myeloma.When the terms "IL-23-, IL-12- and/or IFNa-associated condition" or "IL-23-, IL-12- and/or IFNa-associated disease or disorder" are used herein, each is intended to encompass all of the conditions identified above as if repeated at length, as well as any other condition that is affected by IL-23, IL-12 and/or IFNa.The present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof a therapeutically-effective amount of at least one compound of Formula I or a salt thereof. "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is WO 2020/092196 PCT/US2019/058268 effective when administered alone or in combination to inhibit IL-23, IL-12 and/or IFNa function and/or treat diseases.The methods of treating IL-23-, IL-12 and/or IFNa-associated conditions may comprise administering compounds of Formula I alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions. Accordingly, "therapeutically effective amount" is also intended to include an amount of the combination of compounds claimed that is effective to inhibit IL-23, IL-12 and/or IFNa function and/or treat diseases associated with IL-23, IL-12 and/or IFNa.Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), Interleukin- 10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®); anti-malarials such as hydroxychloroquine; cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or RAPAMUNE®) or derivatives thereof.The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds. The present invention also provides pharmaceutical compositions capable of treating IL-23-, IL-12- or IFNa-associated conditions by inhibiting Tyk2-mediated signal transduction, including IL-23-, IL-12- and/or IFNa-mediated diseases, as described above.The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g., excipients, binders, preservatives, stabilizers, flavors, etc.) WO 2020/092196 PCT/US2019/058268 according to techniques such as those well known in the art of pharmaceutical formulation.Accordingly, the present invention further includes compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agent- containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 17th Edition (1985), which is incorporated herein by reference in its entirety.The compounds of Formula I may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin- related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated. For example, the compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aq. or non-aq. solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds WO 2020/092196 PCT/US2019/058268 may be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.Exemplary compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene).Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may also be orally delivered by sublingual and/or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ@); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanedi 01, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and WO 2020/092196 PCT/US2019/058268 suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.The therapeutically-effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-2mg/kg; 250-1000 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. Thus, when the term "patient" is used herein, this term is intended to include all subjects, most preferably mammalian species that are affected by modulation of IL-23, IL-12 and/or IFNa-mediated functions.
METHODS OF PREPARATIONThe compounds of the present invention may be synthesized by many methods available to those skilled in the art of organic chemistry. General synthetic schemes for preparing compounds of the present invention are described below. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to prepare the compounds disclosed herein. Different methods to prepare the compounds of the present invention will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence in order to give the desired compound or compounds. Examples of compounds of the WO 2020/092196 PCT/US2019/058268 present invention prepared by methods described in the general schemes are given in the preparations and examples section set out hereinafter.
EXAMPLESPreparation of compounds of Formula (I), and intermediates used in the preparation of compounds of Formula (I), can be prepared using procedures shown in the following Examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these Examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula (I) can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature.In the Examples given, the phrase "dried and concentrated" generally refers to drying of a solution in an organic solvent over either sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (generally under reduced pressure and at a temperature suitable to the stability of the material being prepared). Column chromatography was performed with pre-packed silica gel cartridges using an Isco medium pressure chromatography apparatus (Teledyne Corporation), eluting with the solvent or solvent mixture indicated. The following abbreviations are used: Abbreviations Abbreviation MeaningAc acetylACN acetonitrileAcOH acetic acidanhyd. anhydrousaq. aqueousBn benzylBu butylBoc tert-butoxy carb onylBOP benzotri azol-l-yloxytris-(dimethylamino)-phosphonium hexafluorophosphateCV Column Volumes WO 2020/092196 PCT/US2019/058268 Abbreviation MeaningDCE di chloroethaneDCM di chloromethaneDIG N, N'-DiisopropylcarbodiimideDMF dimethylformamideDMSO dimethylsulfoxideEtOAc ethyl acetateEt ethylHorH 2 hydrogenh, hr or hrs hour(s)hex hexanei isoISCO automated chromatographyHO Ac or AcOH acetic acidHC1 hydrochloric acidHPLC high pressure liquid chromatographyEC liquid chromatographyLiHMDS Lithium bis(trimethylsilyl)amideM molarmM millimolarMe methylMeOH methanolMHz megahertzmin. minute(s)mins minute(s)M+l (M+H)+MS mass spectrometryn or N normalnm nanometernM nanomolarPd/C palladium on carbonPh phenylPr propylPSI pounds per square inchrb round bottlert room temperatureRet Time retention timesat. saturatedSEC supercritical fluid chromatographyTBAF Tetra-«-butyl ammonium fluorideTEA triethylamine WO 2020/092196 PCT/US2019/058268 Abbreviation MeaningTFA trifluoroacetic acidTHE tetrahydrofuranXantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene PreparationsThe preparations set out below are for the synthesis of reagents that were not obtained from commercial sources and were employed for the preparation of compounds of formula I of the invention. All chiral compounds in the Tables and Schemes are racemic unless specified otherwise.Reverse-phase preparative high performance liquid chromatography ("HPLC") was performed with Shimadzu 8A liquid chromatographs using YMC S5 ODS columns (20 x 100, 20 x 250, or 30 x 250 millimeter ("mm")). Gradient elution was performed with methanol ("MeOH")/water mixtures in the presence of 0.1% trifluoroacetic acid ("TFA").
HPLC Methods Method A:Column: Waters Acquity BEH C18 2.0 x 50 mm, 1.7 pm; mobile phase A: water with 0.1% TEA; mobile phase B: MeCN with 0.1% TFA; temperature: 40 °C; flow rate 1 mL/min; gradient: 0-100% B over 1.5 min, then 0.5 min isocratic at 100% B.QC-ACN-AA-XB: Column: Waters Acquity UPLC BEH Cl8, 2.1 x 50 mm, 1.7-pm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile :water with 10 mM ammonium acetate; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.
Method E:Phenominex Kinetics C18, 2.1 x 50 mm, 2.1-pm particles; Mobile Phase A: 5:acetonitrile :water with 10 mM ammonium acetate; mobile phase A: 10% acetonitrile in WO 2020/092196 PCT/US2019/058268 water with 0.1% TFA; mobile phase B: 90% acetonitrile in water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 2 minutes: UV at 220 nm.
Method F:Column: YMC Combiscreen ODS-A 4.6 X 50mm S-5; 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase A: 10% methanol in water with 0.1% TFA; mobile phase B: 90% methanol in water with 0.1% TFA; temperature: RT; flow rate 1 mL/min; gradient: 0-100% B over 4 min, then 1 min isocratic at 100% B; UV at 254 nm.
Method QC-ACN-AA-XB:Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-um particles; Mobile Phase A: 5:acetonitrile :water with lOmM ammonium acetate; Mobile PhaseB: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.
Method QC-ACN-TFA-XB:Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-um particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:acetonitrile :water with 0.1% trifluoroacetic acid; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.
Method I:Column: Sunfire C18 (4.6 x 150) mm, 3.5pm; Mobile Phase A: 5:95 acetonitrile: water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile: water with 0.05% TFA;Temperature: 50°C; Gradient: 10-100%B over 12 minutes; F10w:l ml/min.
Method TSI:Column: Waters Acquity UPLC BEH C18 (2.1 x 50 mm), 1.7 micron; Solvent A = 100% water with 0.05% TFA; Solvent B = 100% acetonitrile with 0.05% TFA; gradient = 2-98% B over 1 minute, then a 0.5 minute hold at 98% B; Flow rate: 0.8 mL/min; WO 2020/092196 PCT/US2019/058268 Example 1 6-(cyclopropanecarboxamido)-4-((3-(4-((l,l-dioxidothiomorpholino)methyl)-LH- l,2,3-triazol-l-yl)-2-methoxyphenyl)amino)-/V-(trideuteromethyl)pyridazine-3- Step 4 Step 3 Step 1A mixture of 3-bromo-2-methoxyaniline (500 mg, 2.48 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (943 mg, 3.71 mmol), KOAc (729 mg, 7.mmol) and PdC12(dppf) (91 mg, 0.124 mmol) in 1,4-dioxane (10 mL) was degassed by bubbling with nitrogen gas for 10 minutes. The reaction mixture was sealed and heated to 100 °C for 4.5 hours. Upon completion, the reaction was cooled to room temperature and loaded directly onto silica gel plug for purification by column chromatography eluting in Hexanes/EtOAc 0-100%. The desired fractions were concentrated and the material was WO 2020/092196 PCT/US2019/058268 further purified by silica gel column chromatography eluting with DCM/MeOH 0-10% to give 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline. LCMS m/z 250.(M+H)+; HPLC 1r 0.73 min (analytical HPLC Method TSI). 1H NMR (400 MHz, CHLOROFORM-d) 5 7.12 (dd, <7=7.3, 1.7 Hz, 1H), 6.96 - 6.91 (m, 1H), 6.89 - 6.84 (m, 1H), 3.82 (s, 5H), 1.37 (s, 12H).
Step 2:To a solution of 4,6-dichloro-7V-trideuteromethylpyridazine-3-carboxamide (2mg, 1.41 mmol) and 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (387 mg, 1.55 mmol) in THF (6 mL) was added LiHMDS (IM in THF, 3.53 mL, 3.mmol). The reaction vial was stirred at 25 °C for 20 minutes. Upon completion, the reaction was quenched with saturated aqueous ammonium chloride solution and diluted with DCM and water. The aqueous layer was extracted with DCM. The combined organic layer was dried over sodium sulfate, filtered, and concentrated to give crude material that was assumed quantitative of 6-chloro-4-((2-methoxy-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)amino)-7V-trideuteromethylpyridazine-3-carboxamide (1.41 mmol) and used as such. LCMS m/z 422.1 (M+H)+; HPLC /r 1.07 min (analytical HPLC Method TSI).
Step 3A mixture of 6-chloro-4-((2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)amino)-7V-trideuteromethylpyridazine-3-carboxamide (0.11 mmol, crude from Step 2), cyclopropanecarboxamide (50.5 mg, 0.593 mmol), Pd2(dba)3 (10.9 mg, 0.012 mmol), Xantphos (13.7 mg, 0.024 mmol) and C82CO3 (97 mg, 0.296 mmol) in 1,4- dioxane (1 mL) was degassed by bubbling nitrogen gas through the mixture for minutes. The reaction vessel was sealed and heated to 130 °C for 30 minutes. Upon completion, the reaction was cooled to room temperature and loaded directly onto silica gel for purification by column chromatography eluting with DCM/MeOH 0-10% to give the desired product mixed with water soluble impurities. The collected fractions were dissolved in DCM and washed with water three times, dried over sodium sulfate, filtered, and concentrated to afford 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)amino)-N-trideuteromethylpyridazine-3- WO 2020/092196 PCT/US2019/058268 carboxamide (27 mg, 0.057 mmol, 52 % yield) as a yellow solid. LCMS m/z 471.(M+H)+; HPLC tR 0.95 min (analytical HPLC Method TSI). 1HNMR (400MHz, CHLOROFORM-d) 10.90 ם (s, 1H), 9.53 (br. s., 1H), 8.20 - 8.14 (m, 1H), 8.03 (s, 1H), 7.56 - 7.50 (m, 2H), 7.17 (t, 1=7.6 Hz, 1H), 3.82 (s, 3H), 1.79 (ddd, 1=12.3, 7.9, 4.4 Hz, 1H), 1.36 (s, 12H), 1.12-1.07 (m, 2H), 0.92 - 0.86 (m, 2H) Step 46-(cyclopropanecarboxamido)-4-((2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)amino)-7V-trideuteromethylpyridazine-3-carboxamide (20 mg, 0.043 mmol) was suspended in MeOH (0.3 mL), and sodium azide (5.5 mg, 0.085 mmol) and copper(II) acetate (1.9 mg, 0.011 mmol) were added. The reaction was stirred under an atmosphere of air at 65 °C for 2.5 hours. Upon completion, the reaction was cooled to room temperature and sodium ascorbate (2.1 mg, 0.011 mmol) and 4-(prop-2-yn-l- yl)thiomorpholine 1,1-dioxide (29.5 mg, 0.170 mmol) were added sequentially. The reaction was stirred for 2 hours. Upon completion, the reaction was concentrated, taken up in DMF, filtered through a 0.45 micron syringe filter, and purified by preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5- pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 0-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation to give 6-(cyclopropanecarboxamido)-4-((3-(4-((l,l-dioxidothiomorpholino)methyl)-UT- 1,2,3-tri azol-I-y2-(؛-methoxyphenyl )ami no)-A ׳f-tri deuteromethyl pyridazine-3- carboxamide, TFA (11.4 mg, 0.017 mmol, 38 % yield). LCMS m/z 559.3 (M+H)+; HPLC /r 1.18 min (analytical HPLC Method QC-ACN-AA-XB). Select NMR peaks: 1HNMR (500 MHz, DMSO-d6) 5 11.40 (s, 1H), 11.08 (s, 1H), 9.17 (s, 1H), 8.56 (s, 1H), 8.18 (s, 1H), 7.66 (d, Hz, 1H), 7.51 (d, J=1 A Hz, 1H), 7.46 - 7.39 (m, 1H), 4.24 (s, 2H), 2.12 - 2.02 (m, 1H), 0.91 - 0.77 (m, 4H).
The Examples in Table 1 were prepared using a similar procedure used to prepare Example 1. Table 1 WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method < ,N 1 1 0 D f IT 7,0 r^Y^N^D /U ,N H HN N 0° 510.6 511.4 1.19QC- ACN- AA-XB OH < ,N 1 1 A/O ( T O D 7,0 זז f /L ,N H HN N v 441.5 442.3 0.92QC- ACN- TFA-XB °ר، O 0 < ZN 1 1 0 D 7,0 זז f N H , >؛• J HN N 587.7 588.4 0.96QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method h h 1 1 0 D 7,0 ח f /L ,N H HN N 454.5 455.2 0.96QC- ACN- AA-XB EXAMPLE 6 4-((3-(5-(aminomethyl)-l,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)-/V-trideuteromethylpyridazine-3-carboxamide WO 2020/092196 PCT/US2019/058268 Step 1 Step 2 Step 3 OH Step 1:To a solution of 4,6-dichloro-7V-trideuteromethylpyridazine-3-carboxamide (6mg, 2.89 mmol) and 3-amino-2-methoxybenzonitrile (472 mg, 3.18 mmol) in THF (mL) was added LiHMDS (0.5M in 2-MeTHF, 18.52 mL, 9.26 mmol). The reaction vial was stirred at 25 °C for 35 minutes. Upon completion, the reaction was quenched via addition of saturated aqueous ammonium chloride solution, water, and DCM. The aqueous layer was extracted with DCM. The combined organic layer was dried over sodium sulfate, filtered, and concentrated to give material assumed to be quantitative yield of 6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-7V-trideuteromethylpyridazine-3- carboxamide (2.89 mmol). Carried forward as such. LCMS m/z 321.0 (M+H)+; HPLC /r 0.84 min (analytical HPLC Method TSI).
Step 2:The material from Step 1 (6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-7V- trideuteromethylpyridazine-3-carboxamide (2.89 mmol)), cyclopropanecarboxamide (1.23 g, 14.5 mmol), Pd2(dba)3 (0.265 g, 0.289 mmol), Xantphos (0.334 g, 0.578 mmol) and C82CO3 (2.354 g, 7.23 mmol) in 1,4-dioxane (15 mL) was degassed by bubbling WO 2020/092196 PCT/US2019/058268 nitrogen gas through the mixture for 5 minutes. The reaction vessel was sealed and heated to 130 °C for 45 minutes. Upon completion, the reaction mixture was diluted with DCM, filtered through a celite pad, and concentrated. The crude isolate was then purified by column chromatography on silica gel loading in DMF and eluting with DCM/MeOH 0-10% to give fractions containing water-soluble impurities. The desired fractions were combined and washed with water five times, dried over sodium sulfate, and concentrated to afford 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-A- trideuteromethylpyridazine-3-carboxamide in assumed quantitative yield (2.76 mmol). Material was carried forward as such. LCMS m/z 370.1 (M+H)+; HPLC /r 0.78 min (analytical HPLC Method TSI). 1H NMR (400 MHz, DMSO-d6) 5 11.37 (s, 1H), 10.(s, 1H), 9.17 (s, 1H), 8.05 (s, 1H), 7.78 (dd, J=8.0, 1.4 Hz, 1H), 7.61 (dd, J=7.9, 1.5 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 3.91 (s, 3H), 2.13 - 2.01 (m, 1H), 0.90 - 0.75 (m, 4H) Step 3:To a mixture of 4-((3-cyano-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)-A-trideuteromethylpyridazine-3-carboxamide (0.541 mmol) and hydroxylamine hydrochloride (192 mg, 2.76 mmol) in EtOH (15 mL) was added potassium hydroxide (149 mg, 2.65 mmol). The mixture was sealed and heated to 80 °C. After 24 hours, another aliquot of hydroxylamine hydrochloride (192 mg, 2.76 mmol) and potassium hydroxide (149 mg, 2.65 mmol) were each added and the reaction was heated for 90 minutes more at 80 °C. Upon completion, the reaction was cooled to room temperature, concentrated, taken up in DCM with a small amount of MeOH and filtered through a pad of celite. The filtrate was concentrated to give material in assumed quantitative yield of (Z)-6-(cyclopropanecarboxamido)-4-((3-(A- hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-A-trideuteromethylpyridazine-3- carboxamide (0.541 mmol). Material was used as such. LCMS m/z 403.1 (M+H)+; HPLC Zr 0.55 min (analytical HPLC Method TSI).
Step 4:A portion of the material (1/10) from Step 3 ((Z)-6-(cyclopropanecarboxamido)-4- ((3-(A'-hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-A-trideuteromethylpyridazine- 3-carboxamide (0.0541 mmol)) was suspended in DMF (0.5 mL) with 2-((/erL WO 2020/092196 PCT/US2019/058268 butoxycarbonyl)amino)acetic acid (19 mg, 0.108 mmol). To this mixture was added DIC (0.020 mb, 0.130 mmol) at room temperature, and the reaction was stirred for 90 minutes. Then, TBAF (IM in THF, 0.249 mL, 0.249 mmol) was added in a single portion. After hours, another aliquot of TBAF (IM in THF, 0.12 mL, 0.12 mmol) was added. After hours, the reaction was quenched via the addition of a few drops of saturated aqueous ammonium chloride solution, water and DCM. The aqueous layer was extracted four times with 4/1 CHCl3/iPrOH, and the combined organic layer was washed with water, dried over sodium sulfate, filtered and concentrated to afford material in assumed quantitative yield of ZerLbutyl ((3-(3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-l,2,4-oxadiazol-5- yl)methyl)carbamate (0.0541 mmol). Used as such. LCMS m/z 542.3 (M+H)+; HPLC /r 1.71 min (analytical HPLC Method QC-ACN-AA-XB).
Step 5:Half of the material from Step 4 (ZerLbutyl ((3-(3-((6- (cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2- methoxyphenyl)-!, 2,4-oxadiazol-5-yl)methyl)carbamate (0.0270 mmol) was suspended in DCM (0.5 mL) and TFA (0.5 mL) and stirred at room temperature for 1 hour. Upon completion, the reaction was concentrated. The crude residue was taken up in DMF with a few drops of Et3N to quench residual TFA. The material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5- pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 5- 55% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation to give 4-((3-(5-(aminomethyl)-l,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)-A-trideuteromethylpyridazine-3-carboxamide (1.2 mg, 2.pmol, 9.66 % yield). LCMS m/z 442.3 (M+H)+; HPLC fe 1.11 min (analytical HPLC Method QC-ACN-AA-XB). 1H NMR (500 MHz, DMSO-d6) 5 11.34 (s, 1H), 11.00 (s, 1H), 9.13 (s, 1H), 8.12 (s, 1H), 7.69 (m, 2H), 7.39 (t, J=8.0 Hz, 1H), 4.20 (s, 2H), 3.73 (s, 3H), 2.11-1.98 (m, 1H), 0.89 - 0.71 (m, 4H).
WO 2020/092196 PCT/US2019/058268 The Examples in Table 2 were prepared using a similar procedure used to prepare Example 6. Table 2 Ex.No.Structure MWObs. MS IonRTQC Method ד Y Y! a 0 D f jj JD /k ,N H HN N Y° 511.6 512.1 0.86QC- ACN- TFA-XB o o, z - z y— <1 z / = ' X N״ I Z J ? 494.5 495.1 1.33QC- ACN- AA-XB 0 Anh, N=/ o o A ZNH 542.6 543.1 1.45QC- ACN- AA-XB o / ir o C > ] " z z X D ך 1 1 z A i 542.6 543.3 1.12QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method IO^NH, I1 y r ] o* s xY—J ך! T N to^nh2 °- N، 0H558.6 559 0.98QC- ACN- TFA-XB Vr Y! U Dד,□ זז rYYn^d/L ,N H HN N 559.6 560.3 1.48QC- ACN- AA-XB 0.nhn 'N=—NH P" < N'O H ° °' LJ564.6 565.3 1.26QC- ACN- TFA-XB o Z>° V9MT । ri^Y/ 0^׳^NH 0 D D 0• ,N HHN NA 568.6 569.3 1.52QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method o N^N T । Y/0 0 D rןז jd N H HN N 588.7 589.5 1.42QC- ACN- AA-XB V _ 3 , o Y ־ Z . V — Z O —Y °IZס ס 525.5 526.2 1.45QC- ACN- AA-XB =) 0 ؟ y Y!&° ^^NH 0 D D )^ךז^א׳^ס .N H HN N Y° 483.5 484.3 1.16QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method D D ox NH N= n— N' >— NHP <1 2=(n-o 0 Xn^ 0 H 580.7 581.3 1.05QC- ACN- AA-XB 19 / o z x 0 = 7 H ° Z h ך z z ^ i 513.5 514.3 1.37QC- ACN- AA-XB 9.0 o 0Y >9 Y! a O D r^Y^'N'^'D N H HN N Y° 573.6 574.3 1.11QC- ACN- TFA-XB D D 9XYd /—NH ,nY ° y^~Nv_/°~ n YNH C-A 566.6 567.4 1.1QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method o 0=( ¥9 Y! u ^^NH 0 D WNp zk-,n H HN N Y° 602.6 603.2 1.43QC- ACN- AA-XB Q C V9 N^N T । ^^NH 0 D D r^Y^N^D xk,n H HN N ¥° 539.6 540.4 1.27QC- ACN- AA-XB / —N NH 0Y ؟ Y Y׳ u 0 D D /k,n H HN N xY° 580.7 581.3 1.16QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method C°J =) 0 V9 N^N T । J/O '^^ NH 0 D t.d ןז f 1AfSYD / L ,N H HN N ״ Y 553.6 554.3 1.33QC- ACN- AA-XB D D o yd>—NH^J-NH /°־־ >׳'؟ 4 H K TNH Y/ —Yy ° on~v594.7 595.4 0.86QC- ACN- TFA-XB Y! 4° 0 D JI JLYd /L , N H HN N 567.6 568.3 1.38QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method HNX X., h ^-^NH 0 D ° LI 1 1 o N^N 565.6 566.5 1.16QC- ACN- TFA-XB o =O N^N T । A./0 r r 0 D D /L ,N H HN N ،،° 553.6 554.3 1.42QC- ACN- AA-XB D D °x y-d /—NH N=Z ° /°~ N'L ^؛-^~ 0 N J^NH <1 ،/ A H X/ N'° 499.5 500.1 1.14QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 0= NH N^N I I /L/O ( Y ^^NH 0 D D /U ,N H HN N 483.5 484.1 0.99QC- ACN- TFA-XB >° 0 NH ؟ v N^N T । /k/° ( Y O D D Yx״־ynyd Y ,N H HN N 519.6 520.1 1.08QC- ACN- TFA-XB D D Yd ؟ /~NH N=/ ° Vy~nY/0-־ nVYoX ־ n ؟^ Ynh ZV/nk H ،/א 1 > X/ — N'° 541.6 542.2 1.49QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method V° N^N I 1 0 D D N H HN N A 610.7 611.4 1.85QC- ACN- AA-XB ؟ v N^N I 0X/° LI ^^NH 0 D D INp ,N H HN N 0° 510.6 511.2 0.94QC- ACN- TFA-XB 36 o O. z - z y —< 1z 7 /=7 X 5 ־ IZ o y 522.5 523.3 0.94QC- ACN- TFA-XB 0. nh2 N= n— N' >—NH ° 0 0 ZN0 549.6 550.3 0.96QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 38 p ,tn ° Z I 0 . 1 c m I n J T ך 502.5 503.2 1.1QC- ACN- AA-XB I O^NH A A NyANA^N H I H 7 O^NH, °- N'O 0^ 551.6 552.4 0.95QC- ACN- TFA-XB o o. z - z y— <1 W ׳ W , ־ z . ) = ' 1 1 3 ־ I Z A 571.6 572.2 1.35QC- ACN- AA-XB Q y~NH O 555.6 556.2 1.46QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 0 Knh ,N= °~ Vn °x^N n^0 D D ך ך 0 k^N^/k^/x^ 581.6 582.3 1.64QC- ACN- AA-XB O )NH N—/ HN׳ °' X-d°Yn dV H 569.6 570.3 1.37QC- ACN- TFA-XB 44,,ס ° " ' z - o ^ / t c m T nI O ^ v A x 0^ T z 516.5 517.1 1.32QC- ACN- AA-XB o N =O /y? Nx^N I 1 ^k/° LI 0 D D /L ,N H HN N 567.6 568.4 1.32QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 46 ,p x tn ° Z I 0 . ^ 1 C M / /) J O ^ ^ X ^ X x O < ^ X 7 516.5 517.2 1.21QC- ACN- AA-XB 47 ,p ° z i 0 . 1 c m I n j O * A ך ! 1 516.5 517.1 1.21QC- ACN- AA-XB 0. nh2n'N=Vnh /O— < >U N-0 H o 6' 516.5 517.2 1.2QC- ACN- AA-XB o NH2 N=/ 0 /A XNH <1 W^x n H l — N'° 528.5 529.2 1.25QC- ACN- AA-XB Oz~nh N=/ o 0- O 1 ،NH530.6 531.1 1.14QC- ACN- TFA-XB 51 ,p ,< n° V - ° x ^ x T n J O ^ X / X x J i ך z z ^ s O 530.6 531.2 1.41QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 52° 'z - N T n Iר « 530.6 531.1 1.22QC- ACN- TFA-XB 53o /- A > zV؛ C D * Z IT / = ^ 7־ . ? A r A° z ־ z ، — | 542.6 543.1 1.37QC- ACN- AA-XB 54o>؛ — o x z -z yV V / W״ z . )= ^ 3i? IZ/0^ A 542.6 542.9 1.28QC- ACN- TFA-XB 0/~nh2N=/°. $>T/0' ףV NHA A / V A 1 0 FX/ N'O 1584.5 585 1.56QC- ACN- AA-XB oA-nhO mA ، h2N ;N= O— °X^NH X>y Nx^ 0/ 538.6 539.2 1.36QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method O' nhNp n—,° NH — < ׳ mv >=0ד । P™ 58Y ^ oK Z -O o״ ^ __ 544.6 545.2 1.27QC- ACN- TFA-XB 59o ^zV ° x J .
Iך // ^ ץ -, 0 530.6 531.2 1.38QC- ACN- AA-XB O'nh2Np n —>—NH P V7v ?=Crov y 0 0 0542.6 543.2 1.22QC- ACN- TFA-XB O' nhNp n —>—NH P ״<1 N^j/ >P N~O X kN" CH"^?0544.6 545.4 1.23QC- ACN- TFA-XB 62o o z -z y — o ^ 2o ؛- " / p ° 558.6 559.1 1.14QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex. No.Structure MWObs. MS IonRTQC Method 63 o >؛| — ox z - z y z / = ' x 5 ־ I Z 452.5 453.1 1.34QC- ACN- AA-XB 64 o ox z - z y— <1 V z z ' ) = ' X 5 ־ I Z 487.5 488 0.96QC- ACN- TFA-XB >° ° N- V9 N^N I 1 0 D D r^Y^N^D ,X ,N H HN N V^° 533.6 534.1 1.17QC- ACN- TFA-XB 66 o o z - z y— <1 V zz ) = ' 3 ־ 5 ־ i z / ° ^ 558.6 559.3 0.93QC- ACN- TFA-XB I O^NH VnVyV H । " / o^nh2 °- N'O °' 439.4 440.1 1.37QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method o o x z -z y —<1V z ׳ W ,z / = ' 1r? IZ /0 y 0 Y J 528.5 529.1 1.26QC- ACN- AA-XB OH N^NT ।( Y O D7,0 ח rן^^^^׳׳׳־^סx، ,N H HN N 442.5 443.3 0.95QC- ACN- TFA-XB 70o o, z -z y — 456.5 457.2 1.65QC- ACN- AA-XB QyK>° ס ס 470.5 471 1.18QC- ACN- TFA-XB no^-o N^N T । ,،,( T ^^NH 0 D x، ,N HHN N 468.5 469.3 1.39QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method OH (X N-( 's>. Vo n ؟' z ° n Jx/O LI 0 D D /L ,N H HN N 575.6 576.2 1.06QC- ACN- TFA-XB 0=0 V9 N ^N I 1 0 D D r^Y'^N'^D N H HN N 545.6 546.2 1.11QC- ACN- TFA-XB דד ^0 w N^N I 1 ׳،׳° x ( T ^^NH 0 D r^Y^N^D /L ,N H HN N V^° 511.5 512.2 1.24QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method y° °l V9 N^N I 1 /k/0 ( Y 0 D D Y ״N H HN N Y،° 518.6 519.3 1.08QC- ACN- AA-XB nY. Y N^N Y । /k/0 ( Y ^^NH O D D /L ,N H HN N 509.5 510.3 1.37QC- ACN- TFA-XB OH Y N^N Y । LI ^^NH 0 D D rYx׳YNYD /L ,N H HN N 497.5 498.2 1.11QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method r^o N^N T । a,o ( T ^^NH O D D /L ,N H HN N 482.5 483.2 1.31QC- ACN- AA-XB HO L ؟ v N^N T । _d.o LI ^/^NH 0 D D xL ,N H HN N V^° 511.6 512.2 0.79QC- ACN- TFA-XB OH d V9 v! uc° ^"/NH O D 7,0 ח Y x، , N H HN N 525.6 526 1.22QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method - % ! ס ס 456.5 457 1.29QC- ACN- TFA-XB H0" V9 Y! q ° 0 D 7,0 זז r ,N H HN N Y° 456.5 457 1.46QC- ACN- AA-XB V9 y! U O D HN N 469.5 470.4 1.23QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method Y Y! &° NH 0 D HN N 457.5 458.3 1.53QC- ACN- AA-XB Xo Y Y u ^^NH O D HN N 443.5 444 1.12QC- ACN- TFA-XB ، Y Y, u ^^NH 0 D YYY" HN N 483.5 484.2 1.73QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method / L Y׳ a 0 D A** HN N A° 469.5 470.2 1.43QC- ACN- AA-XB <0 Vs N^N T । ( Y ^^NH 0 D _ HN N A° 469.5 470.2 1.56QC- ACN- AA-XB ؟ v N^N Y । A^nH 0 D HN^N xA 567.6 568.2 1.42QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 93 Q Q 455.5 456 1.08QC- ACN- TFA-XB y° ° N— N^N T । ( Y 0 D HN N Y° 532.6 533.2 1.31QC- ACN- AA-XB °ל، o V9 N^N T । /U/° ( Y 0 D _ HN־^N^ Y° 587.7 588 1.5QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method N^N T ।( Y ^^NH 0 D _ HN N vY 510.6 511.1 1.29QC- ACN- AA-XB 97ם םq Y zx 544.6 545.1 1.3QC- ACN- AA-XB OH Y N^N T ।( Y ^^NH 0 D HN N 441.5 442.2 1.19QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 99ם םq 3 < 9 _ = / 1 478.5 479.1 1.5QC- ACN- AA-XB 100 <0 V9 N^N I 1 0 D A** HN N r^N Jk i| 492.6 493.2 1.79QC- ACN- AA-XB 101 °VNHh ~o N-O v v Q 410.4 411.1 1.1QC- ACN- AA-XB 102 . 0 nh2 — 0 / NH y-، ,N~o FX—// h s< N > א / )' T >^ ^ / ־ /= N ]< 'S ~/ O N 465.5 466.4 0.76QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex. No.Structure MWObs. MS IonRTQC Method 103 "o n-oxMU O487.5 488.2 0.7QC- ACN- TFA-XB 104 M° Q P-N Q/ H2NyO IM'UU Un 467.5 468.4 1.12QC- ACN- AA-XB 105O , z -z U m v z z ' / = / ' r? IZ U u O 483.5 484.1 1.15QC- ACN- AA-XB 106 O^NH2 x. ،, n % /—Y H 9 U /Y o XNy،/YT !ן !ן r438.4 439.2 0.88QC- ACN- AA-XB 107 nh2A nAnAA/N o^nh2 °- N'O426.4 427.4 0.91QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 108O , z-z y v / V z z' /= ' 5־f? IZ / ° ^ O 425.5 426.3 0.51QC- ACN- TFA-XB 109 nh2A Ci NN-N__ Ah, °- NVN ,O oA 503.5 504.2 0.95QC- ACN- AA-XB 110-Zr '2L J I C C I r " o o- 419.4 420.3 0.85QC- ACN- AA-XB 111// ^ o c ^o —IZZ ^ = I ---//O z -z 411.4 412.2 0.99QC- ACN- AA-XB 112z -z o // _'= zZ I r? J J c n " x /wo 488.5 489.2 1.05QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 113 o x $ X/ M / = < z //—Az -z o 468.5 469.4 1.14QC- ACN- AA-XB 114z -z o // __# '=< zZ I 5־/ = ( / >=Z 439.4 440.4 0.91QC- ACN- AA-XB 115 o x"VNH2 N= n— ))— NH Pv HZi ״h/ (=/nAN-A/N^/481.5 482.2 0.73QC- ACN- AA-XB 116O x Z-ZV z" Z . ) = ' «־5־ IZ o ^ z .2 z o 467.5 468.3 0.55QC- ACN- TFA-XB 117 o x nh2 N= n— m׳ )>—NH P J 466.5 467.2 0.79QC- ACN- AA-XB 118 ^ .O° Z I T nJ V i A 474.5 475.1 1.13QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Example 120 Ex.No.Structure MWObs. MS IonRTQC Method 119ץ״ס .ס xz O ' 488.5 489.3 1.22QC- ACN- AA-XB 4-((3-(3-((4-acetylpiperazin-l-yl)methyl)-l,2,4-oxadiazol-5-yl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-trideuteromethylpyridazine- 3-carboxamide Step 1 x WO 2020/092196 PCT/US2019/058268 Step 1:A mixture of tert-butyl piperazine- 1-carboxylate (0.931 g, 5 mmol), bromoacetonitrile (0.348 mb, 5.00 mmol) and potassium carbonate (1.037 g, 7.50 mmol)in DMF (20 mL) was stirred at rt for 18 hr. The reaction mixture was partitioned between EtOAc (75 ml) and water (75 ml). The organic layer was washed with 10% LiCl solution (2 x 75 ml) and brine (75 ml). After drying (Na2SO4) and filtration, the organic layer was concentrated to afford tert-butyl 4-(cyanomethyl)piperazine-l-carboxylate (1.08 g, 4.mmol, 96 % yield) as a dark yellow solid. 1H NMR (400MHz, chloroform-d) 5 3.53 (s,2H), 3.51 - 3.45 (m, 4H), 2.60 - 2.47 (m, 4H), 1.47 (s, 9H).
Step 2:A mixture of tert-butyl 4-(cyanom ethyl )piperazine- 1 -carboxylate (1.07 g, 4.mmol), hydroxylamine hydrochloride (0.495 g, 7.12 mmol) and sodium bicarbonate(0.798 g, 9.50 mmol) in tert-BuOH (20 mL) was stirred at 80 °C for 4 hr. After coolingto rt, the reaction mixture was partitioned between EtOAc (75 ml) and water (75 ml). The organic layer was washed with brine (50 ml), dried (Na2SO4) and concentrated to afford (Z)-tert-butyl 4-(2-amino-2-(hydroxyimino)ethyl)piperazine-l-carboxylate (987 mg, 3.
WO 2020/092196 PCT/US2019/058268 mmol, 80 % yield) as a white solid. 1H NMR (400MHz, DMSO-d6) 5 8.97 (s, 1H), 5.(s, 2H), 3.38 - 3.27 (m, 6H), 2.32 - 2.25 (m, 4H), 1.43 - 1.35 (m, 9H).
Step 3:A mixture of methyl 2-hydroxy-3-nitrobenzoate (6 g, 30.4 mmol), iodomethane (3.81 mL, 60.9 mmol) and potassium carbonate (10.52 g, 76 mmol) in DMF (100 mL) was stirred at rt for 3 days. Ice water (500 ml) was added and the resulting suspension was stirred for 30 minutes. Filtration and drying afforded methyl 2-methoxy-3- nitrobenzoate (5.17 g, 24.48 mmol, 80 % yield) as a white solid. LCMS m/z 219.(M+H)+; HPLC 1r 1.46 min (analytical HPLC Method F); 1H NMR (400MHz, chloroform-d) 5 8.03 (dd, 1=7.9, 1.8 Hz, 1H), 7.91 (dd, 1=8.1, 1.8 Hz, 1H), 7.31 - 7.(m, 1H), 4.01 (s, 3H), 3.96 (s, 3H).
Step 4:A mixture of methyl 2-methoxy-3-nitrobenzoate (5.16 g, 24.44 mmol) and NaOH, IN (51.3 mL, 51.3 mmol) in MeOH (200 mL) was stirred at rt for 18 hr. The MeOH was removed on the rotovap and the remaining solution was diluted with 100 ml of water. The pH was adjusted to 1 with IN HC1 and the resulting suspension was filtered and dried to afford 2-m ethoxy-3-nitrobenzoic acid (4.65 g, 23.59 mmol, 97 % yield) as a white solid. LCMS m/z 198.0 (M+H)+; HPLC 1r 1.01 min (analytical HPLC Method F); 1H NMR (400MHz, chloroform-d) 5 8.30 (dd, 1=7.9, 1.8 Hz, 1H), 8.04 (dd, 1=8.1, 1.8 Hz, 1H), 7.38 (t, 1=7.9 Hz, 1H), 4.09 (s, 3H) carboxylic acid proton not seen.
Step 5:To a mixture of 2-methoxy-3-nitrobenzoic acid (4.55 g, 23.08 mmol), 4- dimethylaminopyridine (0.282 g, 2.308 mmol) and tert-butanol (3.31 mL, 34.6 mmol) in DCM (200 mL) at 0 °C was added di cyclohexylcarbodiimide (4.76 g, 23.08 mmol) in portions. The reaction mixture was allowed to warm and was stirred at rt for 16 hrs. After filtration through celite, the filtrate was washed with IN HC1 (2 x 200 ml) and brine (2ml). After drying (MgSO4) and filtration the organic layer was concentrated to a yellow semi-solid that was chromatographed on a 120 gm ISCO silica gel cartridge, eluting with a 0-30%EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl 2- m ethoxy-3-nitrobenzoate (5.11 g, 20.18 mmol, 87 % yield) as a light yellow oil. 1H WO 2020/092196 PCT/US2019/058268 NMR (400MHz, chloroform-d) 5 7.94 (dd, 1=7.9, 1.8 Hz, 1H), 7.87 (dd, 1=7.9, 1.8 Hz, 1H), 7.30 - 7.20 (m, 1H), 4.00 (s, 3H), 1.63 (s, 9H).
Step 6:A mixture of tert-butyl 2-methoxy-3 -nitrobenzoate (5.1 g, 20.14 mmol) and 10% Pd/C (1.072 g, 1.007 mmol) in ethyl acetate (200 ml) was stirred under an atmosphere of hydrogen at rt for 16 hr. Filtration through a 0.45 micron nylon filter and concentration of the filtrate afforded tert-butyl 3-amino-2-methoxybenzoate (4.50 g, 20.16 mmol, 100% yield) as a yellow oil, The material became a crystalline solid upon standing. 1H NMR (400 MHz, chloroform-d) 5 7.11 (dd, >1.8 י ה ר Hz, 1H), 6.96 - 6.89 (m, 1H), 6.88 - 6.(m, 1H), 3.90 (br s, 2H), 3.84 (s, 3H), 1.60 (s, 9H) Step 7:To a solution of 4,6-dichloro-A-trideuteromethylpyridazine-3-carboxamide (see previuos patents for preparation) (1g, 4.78 mmol) and tert-butyl 3-amino-2- methoxybenzoate (1.067 g, 4.78 mmol) in THF (30 mL) at rt was added dropwise over minutes LiHMDS, IM in (11.96 mL, 11.96 mmol). The resulting solution was stirred at rt for 10 minutes. The reaction mixture was quenched with 10 ml of saturated ammonium chloride solution. The resulting mixture was partitioned between EtOAc (150 ml) and saturated ammonium chloride solution (150 ml). The organic layer was washed with brine (150 ml), dried (Na2SO4) and concentrated to an amber oil that was chromatographed on a 80 gm ISCO silica gel cartridge, eluting with a 0-60%EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl 3-((6-chloro-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate (1.60 g, 4.mmol, 84 % yield) as a light yellow solid. LCMS m/z 396.4/398.2 (M+H)+; HPLC /r 2.93 min (analytical HPLC Method F) Step 8:A mixture of tert-butyl 3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4- yl)amino)-2-methoxybenzoate (1.2 g, 3.03 mmol), cyclopropanecarboxamide (0.516 g, 6.06 mmol), Pd2(dba)3, chloroform adduct (0.313 g, 0.303 mmol), Xantphos (0.351 g, 0.606 mmol) and C82CO3 (3.95 g, 12.13 mmol) in Dioxane (20 mL) was degassed by WO 2020/092196 PCT/US2019/058268 bubbling nitrogen through the mixture for 5 minutes. The reaction vessel was sealed and heated to 130 °C for 6 hr. After cooling to rt, the reaction mixture was partitioned between EtOAc (100 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (50 ml) and the combined organics were dried (Na2SO4) and concentrated to afford a yellow oil that was chromatographed on a 80 gm ISCO silica gel cartridge, eluting with a 0-100%EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl 3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate (1.01 g, 2.2mmol, 75.0 % yield) as a yellow solid. LCMS m/z 445.5 (M+H)+; HPLC Zr 2.59 min (analytical HPLC Method F).
Step 9:A mixture of tert-butyl 3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate (1.01 g, 2.2mmol) and HC1, 4N in dioxane (5.68 mL, 22.72 mmol) in DCM (10 mL) was stirred at rt for 8 hr. The reaction mixture was allowed to stand in the freezer for 3 days. The volatiles were removed in vacuo and the residue was dried to afford ((6- (cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2- methoxybenzoic acid, HC1 (0.96 g, 2.260 mmol, 99 % yield) as a yellow solid. LCMS m/z 389.3 (M+H)+; HPLC t K 1.48 min (analytical HPLC Method F).
Step 10:A mixture of 3-((6-(cyclopropanecarboxamido)-3-(trideutero- methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoic acid (350 mg, 0.901 mmol), (Z)-tert-butyl 4-(2-amino-2-(hydroxyimino)ethyl)piperazine-l -carboxylate (233 mg, 0.901 mmol), 3-(Ethyliminomethyleneamino)-A,A-dimethylpropan-l-amine, HC1 (1mg, 0.991 mmol), 1-hydroxybenzotriazole (152 mg, 0.991 mmol) and triethylamine (3pl, 2.70 mmol) in DMF was stirred 18 hr at rt. An additional amount equal to half of the initial aliquot of each reagent (except starting material) was added and stirring was continued at rt for 3 days. An additional amount of (Z)-tert-butyl 4-(2-amino-2- (hydroxyimino)ethyl)piperazine-l-carboxylate (100 mg) was added followed by BOP (199 mg, 0.451 mmol) and the mixture was stirred 1 hr at rt. The reaction mixture was WO 2020/092196 PCT/US2019/058268 partitioned between EtOAc (40 ml) and water (40 ml). The organic layer was washed with 10%LiCl solution (2 x 40 ml) and brine (40 ml). After drying (Na2SO4) and filtration the organic layer was concentrated to afford (Z)-tert-butyl 4-(2-amino-2-(((3- ((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2- methoxybenzoyl)oxy)imino)ethyl)piperazine-l-carboxylate (565 mg, 0.899 mmol, 100 % yield) as a yellow solid. LCMS m/z 629.5 (M+H)+; HPLC Zr 2.28 min (analytical HPLC Method F).
Step 11:A mixture of (Z)-tert-butyl 4-(2-amino-2-(((3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoyl)oxy) imino)ethyl)piperazine-l-carboxylate (565 mg, 0.899 mmol) and tetrabutylammonium fluoride, IM in THF (1.348 mL, 1.348 mmol) in acetonitrile (9 mL) was stirred at rt for hr. The reaction mixture was partitioned between EtOAc (30 ml) and waster (30 ml). An emulsion formed. ~1 gm of NaCl was added and the layers separated. The organic layer was washed with brine (30 ml). After drying (Na2SO4) and filtration, the organic layer was concentrated to afford a yellow oil that was chromatographed on a 24 gm ISCO silica gel cartridge, eluting with a 0-100%EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl 4-((5-(3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-l,2,4-oxadiazol-3- yl)methyl)piperazine-l-carboxylate (213 mg, 0.349 mmol, 38.8 % yield) as an off-white solid. LCMS m/z 611.5 (M+H)+; HPLC Zr 2.35 min (analytical HPLC Method F).
Step 12:A mixture of tert-butyl 4-((5-(3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-l,2,4-oxadiazol-3- yl)methyl)piperazine-l-carboxylate (201 mg, 0.329 mmol) and HC1, 4N in dioxane (0.8mL, 3.29 mmol) in DCM (4 mL) was allowed to stand at rt overnight. Removal of the volatiles in vacuo and drying afforded 6-(cyclopropanecarboxamido)-4-((2-methoxy-3 -(3- (piperazin- 1 -ylmethyl)- 1,2,4-oxadiazol-5-yl)phenyl)amino)-A- trideuteromethylpyridazine-3-carboxamide, HC1 (180 mg, 0.329 mmol, 100 % yield) as a WO 2020/092196 PCT/US2019/058268 yellow solid. LCMS m/z 511.5 (M+H)+; HPLC /r 1.91 min (analytical HPLC Method F).
Step 13:A mixture of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3 -(3-(piperazin- 1- ylmethyl)-l,2,4-oxadiazol-5-yl)phenyl)amino)-A-trideuteromethylpyridazine-3- carboxamide, HC1 (12 mg, 0.022 mmol), acetic anhydride (2.277 pl, 0.024 mmol) and triethylamine (0.012 ml, 0.088 mmol) in DCM (0.25 ml) was agitated at rt for hr. MeOH (0.2 ml) was added and the volatiles were removed in vacuo. The residue was dissolved in DMSO and was purified via preparative LC/MS with the following conditions: Column: waters xbridge c-18, 19 x 100 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-80% B over 12 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 4-((3-(3- ((4-acetylpiperazin-l-yl)methyl)-l,2,4-oxadiazol-5-yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide (10.3 mg, 0.0.018 mmol, 84 % yield) . LCMS m/z 553.2 (M+H)+; HPLC fe 1.25 min (QC-ACN- AA-XB); 1H NMR (500MHz, DMSO-d6) 5 11.36 (s, 1H), 11.05 (s, 1H), 9.16 (s, 1H), 8.12 (s, 1H), 7.83 (d, 1=7.4 Hz, 1H), 7.77 (d, 1=8.1 Hz, 1H), 7.42 (t, 1=7.9 Hz, 1H), 3.(s, 2H), 3.78 (s, 3H), 3.44 (d, 1=4.7 Hz, 1H), 2.55 (d, 1=4.7 Hz, 2H), 2.13 - 2.02 (m, 1H), 1.97 (s, 3H), 0.90 - 0.75 (m, 4H). Missing peaks co-resonate with solvent and water peaks.
The Examples in Table 3 were prepared using a similar procedure used to prepare Example 120. Table 3 WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 121 L Yl &° NH 0 D D N H HN N v^° 440.5 441.3 1.44QC- ACN- TFA-XB 122 t , N^o T । 0 D t,d זז f N H HN N ،° L 468.5 469.3 2.02QC- ACN-AA- XB 123 a, N^o T । ^k/O LI 0 D D t^V^N^D xL ,N H HN N 488.5 489.3 1.74QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 124 YYi uc° 0 D D N H HN N 511.6 512.3 1.33QC- ACN-AA- XB 125 Y.Y! &° NH 0 D HN N 510.6 511.2 1.28QC- ACN-AA- XB 126 NH ؛ o Y Y! &° 0 D D N H HN N Y° 510.6 511.3 1.1QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 127 > ^0 c . N ؟= Yl &° 0 D f ]J 7,0 zL ,N H HN N V^° 582.6 583.2 1.26QC- ACN-AA- XB 128 o L N^o T । ^k/° LI 0 D D r^Y^'N'^'D /U ,N H HN N L،° 588.7 589.3 1.45QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 129 Y ^ : r c v " z ' z O— ° z = ( 1 / = o I Z ס ס 564.6 565.2 1.33QC- ACN-AA- XB 130 0 o N-' Y Y! uC° 0 D 7,0 ך f Yy^'n'^d ,N H HN N Y 615.7 616.2 1.34QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 131 =o c Yl uc° 0 D t،d ך f r^V^N^D N H HN N 615.7 616.4 0.94QC- ACN- TFA-XB 132 d ם 1 rO ־V X p 578.6 579.4 1.53QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 133 Z—SN yo c -1 V' 6c° ^/NH 0 D r^V^N^D xN H HN N A° 603.7 604.2 1.44QC- ACN-AA- XB 134 N L 0 =1 Y! uC° NH 0 D D N H HN N Y° 577.6 578.4 1.41QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 135 °>° c Y V' &° O D 7,0 ך f ,N H HN N A 610.7 611.4 1.94QC- ACN-AA- XB 136 Hr^ o y Y׳ UC° NH 0 D ד,□ זז f xN H HN N Y° 581.7 582.3 1.37QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 137 v° n p0 h Y! uC° O D N H HN N Y° 624.7 625.3 1.7QC- ACN-AA- XB 138 Y O Y Y! Y° ^^NH 0 D f Ji T,D D ־ > ־'' Yr'N ؛ >؛ i Y ,N H HN N Y° 568.6 569.3 1.46QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 139 N Y! UC° O D f jj L.D YyY'ti ,N H HN N A 591.6 592.4 1.17QC- ACN-AA- XB 140 ^0 n <׳،. Y! uC° 0 D D ,N H HN N V^0 566.6 567.3 1.13QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 141 n po Y! uC° 0 D 7,0 זז f xL ,N H HN N v 602.6 603.3 1.25QC- ACN-AA- XB 142 D P 0 y־D y—NH N= n—J >NHP״ V H-p >؛ pH 0 ס o I 541.6 542.3 1.74QC- ACN-AA- XB 143 nh2 V״ N^o T । LI 0 D rזז t,dA'n'><'D ؟ P /L ,N H HN N Y° 441.5 442.2 1.13QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 144 z ' ל — Z O— ־ , ־ = z / = o I Z ) v D ס ס 532.6 533.3 1.67QC- ACN- TFA-XB 145 0=^ NH L N^o T । LI ^^NH O D [ JL L־D /L ,N H HN N 483.5 484.2 1.16QC- ACN-AA- XB 146 y° 0 NH =׳؛ s Y1 6c° O D NNp Jx ,N H HN N 519.6 520.2 1.08QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 147 D D 0 y־D y—NH N= n— >—NHP 4 H Vnh Wn^VY6 S । 526.6 527.2 1.23QC- ACN-AA- XB 148 D D 0 >^D YnH N= n— NHP AV Hytl h r« 508.5 509.2 1.02QC- ACN- TFA-XB 149 o- th 0 V ־ f - W : o ס 539.6 540.2 1.35QC- ACN-AA- XB 150 p- hk h ר >rV' 1 o ^ 3 o ס 567.6 568.3 1.82QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 151 V HN )=N /= mn P־& P X-D N 0 534.6 535.2 1.26QC- ACN-AA- XB 152 D Dy- D 'VnhN= n —>—NH PV ?Vn ״ h K/nANyNo?° o 513.5 514.2 1.05QC- ACN- TFA-XB 153 Dx Po y ־D4—NHN= n —J >—NH PH M-O 8 SVnh n/^/nV^n'^־o/& 1 612.7 613.3 1.5QC- ACN-AA- XB 154 D Do x y ־D ^NHN= n —NH P — .׳ ،V h^NH V-y N'^״'NY׳^N/o H 512.5 513.1 0.81QC- ACN- TFA-XB - Ill - WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 155 D D o y־D y—NH N= n— N' >—NHP 4 v rwx ״ ^NH N'^/ Y^NH2 0 0 498.5 499.2 0.8QC- ACN- TFA-XB 156 h2^=n Y! &° 0 D f JI jD r^S^'N'^D xN H HN N 467.5 468.2 0.86QC- ACN- TFA-XB 157 D D 0 )^D Y—NHN= n—m' >NHP 4 ■K d 1 ^NH VJ7 O o H 598.6 599.3 1.45QC- ACN-AA- XB 158d ם ^ z x T = / = Z s , ° M z M z ־ ° L z . o 539.6 540.1 1.58QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 159 0 A I L 9 n J ^ 4 * 0 568.6 569.1 1.21QC- ACN-AA- XB 160 D D 0TD y—NH N= n— m' >NHP 4 v rQxh TNHVj 7 n'^/ny^n/^ ° O 4-N 581.7 582.1 1.03QC- ACN-AA- XB 161 D D Ox y־D Y—NH N= n- 0 . Vnh ״׳ 4V K-41 ״ y™ 0 0 1-vy 0 1 667.7 668.2 1.13QC- ACN- TFA-XB 162 D D oxT° >—NH N= n— >NH ,° 4 K h TNH V_# ° o INH 567.6 568.3 0.94QC- ACN-AA- XB 163 D p o. y־D >—NH Nz= n— y-NHp 4 K>=V<°1 h —NH V-27 ° O LN, 645.7 646.4 0.94QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 164 0 ؟, o N—' Y Y׳ q ° O D N H HN N Y° 559.6 560.0 1.27QC- ACN-AA- XB 165 X X )= oIZס ס 509.5 510.2 1.07QC- ACN- TFA-XB 166 I ״o ؟= o=cX ( X z ')-Z O— Z = ( Y o IZס ס 545.6 546.3 1.37QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 167 D P 0 NH <1 V >=(, S , o o 1 555.6 556.3 1.65QC- ACN- TFA-XB 168 hS=n. & 0 D f JIt,d ,N H HN N V^° 455.5 456.2 0.85QC- ACN- TFA-XB 169 k° ° N— V" Ny .0 T । ^k/° LI ^^NH 0 D D xL xN H HN N 533.6 534.2 1.23QC- ACN- TFA-XB 170 3. ° Y Z ' I J » ؟ 527.6 528.2 1.29QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 171 3 . o ^ z I 1 n J ؟ "lx ° 522.5 523.2 1.3QC- ACN-AA- XB 172 D D 0yd y—NH a N^T }=_2-N 1Vnh VJ^n/V/nv ^n/ 0 S 1 540.6 541.3 1.26QC- ACN-AA- XB 173 0=( N— Y Y! 6c° ^^NH 0 D D N H HN N Y° 497.5 498.3 1.26QC- ACN-AA- XB 174 OH Y Y! O D f JT L.D ,N H HN N Y° 442.5 443.2 1.18QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 175 D D oxTD y—NH N= n— <1nxj 7 NHX-pn״ ° / 0 0 557.6 558.1 1.58QC- ACN-AA- XB 176 D D 0 ^־D y—NH N= n— x! >—NHP <1NyJ =(0-N o ^ 0 ־׳׳ nh vJ^n^،^n-XXx (^ 0 H 527.6 528.2 1.23QC- ACN-AA- XB 177 D D 0 y־D >—NH N= n— NHP — < .׳ ، <1 Ny7 X=<^ P~N 0 yNHU־^N-Vn^OH 0 H 513.5 514.2 1.09QC- ACN-AA- XB 178 D D o y־D >—NH N= n— J >—NH ,° <1 ij O ^-nh vJ^n^x^n־^ o' H 497.5 498.2 1.06QC- ACN- TFA-XB 179 o £ y, uc° 0 D D /X ,N H HN N V^° 539.6 540.0 1.23QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 180 d N-' Y Y1 uc° 0 D 7,0 ך f N H HN N A 524.6 525.3 1.05QC- ACN-AA- XB 181 H2N—< yN N^O I 1 ^k/° LI ^^NH O D ,N H HN N 455.5 456.0 1.1QC- ACN-AA- XB 182 D P oyd yNH N= n— >—NHP 4V H °^ NY ؟ H vrA ״ y O 1 o 513.5 514.2 1.38QC- ACN-AA- XB 183 0=4 NH ....Y Y! &° O D 7,0 ח r /L ,N H HN N Y° 497.5 498.4 1.01QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 184 ° NH ....Y.
Y! UC° O D f jj T.D Yy^'n'^'d /L ,N H HN N Y° 533.6 534.0 1.32 QC- ACN-AA- XB 185 Q Ynh < /= W PYo ° nV0 nYn / D D Y 0 । ^0YYY 1 1 H 641.7 642.4 2.21 QC- ACN-AA- XB 186 HO / )=N Y! &° ^־^NH 0 D f JI JY N H HN N Y° 470.5 471.2 1.38 QC- ACN-AA- XB 187 RD ، - 9 N^N / V '.. 0 / N hn ? ךXXY Yo ־ xA'N '־ H OH 527.6 528.2 1.16 QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 188 D ט ، p־O fX N^N / V./ 0 V / N X ? HN Y0 H OH <^J 543.6 544.2 1.29QC- ACN-AA- XB 189 -OH h2n*Y Y! uC° 0 D 7,0 זז r YYYd X ,N H HN N Y° 485.5 486.4 1.07QC- ACN-AA- XB 190 d,d /Y °' Y0 PY;o M N < " ؟ O hn ؟ ץ'x־xX'N'x~xY )=O H OH 541.6 542.3 1.04QC- ACN- TFA-XB 191 H2N" M Y׳ uC° ^"^NH 0 D 7,0 זז !יYYn^d N H HN N Y° 455.5 456.4 1.14QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 192 0 P o y־D y—NH N= n—m' >—NHP 4yr ״Ynh 0 ؛ o 513.5 514.2 1.2QC- ACN- TFA-XB 193 D D 0yd y—NH N= n— >NHP ״ Ui (־ H >؛ 1 o ؛ o 555.6 556.3 1.76QC- ACN-AA- XB 194 0=^ NH Y! &° 0 D jd זז ־ 1 YY'iYd /L,n H HN N 497.5 498.2 1.21QC- ACN-AA- XB 195 < 1 J L ^ 533.6 534.2 1.33QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 196 D D o ^NH N=< n—>—NH PV ״y NH؛ o 511.6 512.3 1.32QC- ACN-AA- XB 197 Qnh ؛/- Pl O 0 nVD n' n / D ט0 1 Y Y /<>< MNGOBH 627.7 628.3 1.85QC- ACN- TFA-XB 198 D ט/ ^"DY^N^yNHPY/oN^N /O V / N H ״ n ؛ IIXn/x-'oh >0H 527.6 528.2 1.13QC- ACN-AA- XB 199 טח O^f)o Mn onv n /II ז ^..HNAn/-x/OH xH 513.5 514.1 1.1QC- ACN-AA- XB 200 HN )=N /= wQ~nh ؛؛ W^np-/0 ° nVcם ° / n .Y•^n־'a'^0־y/ h A 555.6 556.0 1.41QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 201 hoh2n—( y=N N^O T । ^^NH 0 D [ jj T.D /L ,N H HN N 471.5 472.2 0.8QC- ACN- TFA-XB 202 D D p־O 0NVN ׳ >N׳ ^n^=hhV0 H 543.6 544.2 0.99QC- ACN- TFA-XB 203 ، D D / O Yp hT)o o v z >N JL Jl HN )=0 H 6h <^j 527.6 528.1 1.16QC- ACN-AA- XB 204 ״OH H2N"< <ץ & 0 D D ,N H HN N 485.5 486.2 1.07QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 205 0 ם °xYd 0 V>=n 11 ״ I HN ° Y ־־־׳H 6h 557.6 558.2 1.07QC- ACN- TFA-XB 206 j - C ? yCQ a . ״ W□Y□ 641.7 642.2 1.99QC- ACN- TFA-XB 207 OH d Y Y! uC° NH 0 D D /U ,N H HN N Y° 525.6 526.2 0.83QC- ACN- TFA-XB 208 D ס / X~D )/NH}—NH9Y;o N^N / V״' 0 Y / N jf I hn'x-/A'n/Y/ )=0 H oh <^ן 541.6 542.2 1.06QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 209 S=*.
Y &° ^NH 0 D d זז r N H HN N 495.6 496.2 1.45QC- ACN-AA- XB 210 b- $=״. Y &° NH 0 D _ HN N b° 538.6 539.2 1.61QC- ACN-AA- XB 211 ) $=״ Y, UC° 0 D 7,0 זז f (ArN^D /L ,N H HN N 523.6 524.2 1.12QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 212 X, & NH 0 D HN N A 466.5 467.2 1.34QC- ACN-AA- XB 213 o ס 566.6 567.1 1.71QC- ACN-AA- XB 214d ם 1 x 4 ^ ° = 1 > / Y d 508.6 509.1 0.91QC- ACN- TFA-XB 215 Y Y! UC° ^^NH 0 D HN N 494.6 495.2 1.51QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 216 & ^^NH 0 D HN N Y° 531.6 532.2 1.83QC- ACN-AA- XB 217 OH Y N^o T । 0 D HN N 441.5 442.1 0.83QC- ACN- TFA-XB 218 HO / )=N Y! uc° ^^NH O D HN N v 469.5 470.2 1.39QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 219 o > ° z C p * Y Y * ס. z ס 627.7 628.4 2.09QC- ACN-AA- XB 220 D D 0 Yp O V >=N N /=O H X513.5 514.3 1.03QC- ACN-AA- XB 221 HO h2n^, N^O T । /k,o O D f jj 7,0 r^V^N^D /، ,N H HN N v 471.5 472.2 1QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 222 ^0 o Y! &° NH 0 D HN N 565.6 566.2 1.28QC- ACN-AA- XB 223 O S=n Y! a° ^^NH 0 D HN N Y° 601.7 602.3 1.4QC- ACN-AA- XB 224.A. =no-p OYVnhVnhV-V 0a u D D 514.6515.5 1.06E WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 225 HO ■u Yl uc° 0 D fזז jd /U ״N H HN N 456.5 457.2 1.31QC- ACN-AA- XB 226 o 4 0 ^ 2 1 L 9 U J " l x ° V 6 512.6 513.2 1.6QC- ACN- TFA-XB 227 D P o y־D y—NH n/==^nh A >=C/O'N 1 )^NH 0' 511.6 512.2 1.76QC- ACN-AA- XB 228 HO ■u uc° ^/^NH 0 D HN N 455.5 456.2 1.11QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 229 V.
N^o T । ^k/Q LI 0 D D r^LL^'N'^D xL ,N H HN N 452.5 453.1 1.86QC- ACN-AA- XB 230 ^ n ؟ o N (= / __ N^O LT O D l.d זז f I^V^N^D N H HN N ،° x 529.5 530.2 1.53QC- ACN-AA- XB 231 dXd' V- N T HN^O X/ HN>r 636.7 637.5 1.92QC- ACN-AA- XB 232 o X — // v ? x / ؟ □ X - z rA x TZ. z^= L p r ^ z $ 536.6 537.2 0.72QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 233 0 e 0 / N 1 N^ HNX^° 7 B X 0 lx HNX^ o 578.6 579.2 1.34QC- ACN-AA- XB 234 1 0 ^ 0 Z O״ y = z O ' ° z x X ? 1 / ^ V - 7 ס O =^ Z־Z ° 594.6 595.4 1.56QC- ACN-AA- XB 235 o ם K X ' qX t / ° x z v _ $ ־ o=w =o 614.7 615.1 1.23QC- ACN-AA- XB 236 o XN N^/O T । LI 0 D D xL xN H HN N 514.6 515.0 2.14QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 237 c =1 Y1 uc° O D N H HN N 535.6 536.3 0.81QC- ACN- TFA-XB 238 x، ^NH 0 D D ,N H HN N /° 551.6 552.3 0.88QC- ACN- TFA-XB Example 239 5-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4- yl)amino)-2-methoxyphenyl)-A^،V-dimethylthiazole-2-carboxamide WO 2020/092196 PCT/US2019/058268 Step 1:A stirred mixture of ethyl 2-bromothiazole-5-carboxylate (116 mg, 0.491 mmol) , 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (135 mg, 0.540 mmol) and l,l'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.01 mg, 0.0mmol) in Dioxane (4 mL) was degassed by bubbling nitrogen through the mixture for minutes. 2M K3PO4 (aq) (0.737 mL, 1.474 mmol) was quickly added and the reaction mixture heated at 100 °C for one hour. LC-MS showed complete conversion to thedesired product mass. The reaction mixture was cooled to room temperature.The reaction mixture was diluted with EtOAc (75mL) and then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography, eluting with 0-100% EtOAc WO 2020/092196 PCT/US2019/058268 in hexanes. This afforded ethyl 2-(3-amino-2-methoxyphenyl)thiazole-5-carboxylate (mg, 0.299 mmol, 60.8 % yield) as a yellow oil.. LCMS m/z 279.2 (M+H)+; HPLC /r 0.min (HPLC Method A).
Step 2:To a solution of 4,6-dichloro-A-trideuteromethylpyridazine-3-carboxamide (mg, 0.297 mmol) and ethyl 2-(3-amino-2-methoxyphenyl)thiazole-5-carboxylate (83 mg, 0.297 mmol) in Tetrahydrofuran (2.5 mL) at rt was added dropwise over 5 minutes LiHMDS, IM (0.741 mL, 0.741 mmol). The resulting solution was stirred at rt for minutes. The reaction mixture was quenched with 1 ml of saturated NH4Cl solution. The resulting mixture was partitioned between EtOAc (30 ml) and saturated NH4C1 solution (30 ml). The organic layer was washed with brine (30 ml), dried (Na2SO4) and concentrated to an amber oil that was chromatographed on a 12 gm ISCO silica gel cartridge, eluting with a 0-60%EtOAc/Hex gradient. The pure fractions were concentrated to afford ethyl 2-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2- methoxyphenyl)thiazole-5-carboxylate (80 mg, 0.176 mmol, 59.2 % yield) as a white solid. LCMS m/z 451.2 (M+H)+; HPLC 1r 1.02 min (analytical HPLC Method A).
Step 3:A mixture of 4-(3-((2-chloro-5-(trideuteromethylcarbamoyl)pyridin-4-yl)amino)- 5-fluoro-2-methoxyphenyl)-N-(2-methoxyethyl)thiazole-2-carboxamide (80 mg, 0.1mmol), Xantphos (20.53 mg, 0.035 mmol), and cyclopropanecarboxamide (75 mg, 0.8mmol) in dioxane (3 mL) was degassed by bubbling N2 through it for 5 minutes. Then C82CO3 (231 mg, 0.710 mmol) and Pd2(dba)3 (16.25 mg, 0.018 mmol) were added, the vessel was sealed, and the reaction was stirred at 130 °C for 45 minutes. The reaction was complete by LC-MS. The reaction was cooled to room temperature, then concentrated and loaded directly onto a 12g ISCO column for purification by flash chromatography, eluting with 0-15% MeOH in DCM. This afforded ethyl 2-(3-((6- (cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2- methoxyphenyl)thiazole-5-carboxylate (66 mg, 0.129 mmol, 73.0 % yield) as a pale yellow solid. LCMS m/z 500.2 (M+H)+; HPLC /r 0.89 min (analytical HPLC Method A) WO 2020/092196 PCT/US2019/058268 Step 4:To a solution of ethyl 2-(3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)thi azole-5- carboxylate (41 mg, 0.082 mmol) in THF (2 ml) was added a solution of lithium hydroxide, H2O (4.13 mg, 0.098 mmol) in water (0.5mL). The resulting solution was stirred at room temperature over the weekend. The volatiles were removed in vacuo to afford 2-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4- yl)amino)-2-methoxyphenyl)thiazole-5-carboxylic acid, lithium salt (38 mg, 0.081 mmol, % yield) as a yellow solid. Used as is. LCMS m/z 472.4 (M+H)+; HPLC /r 0.72 min (analytical HPLC Method A).
Step 5:A mixture of 2-(3-((6-(cyclopropanecarboxamido)-3-((methyl- d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)thiazole-5-carboxylic acid, lithium salt (13 mg, 0.028 mmol) , dimethylamine, 2M in THF (0.069 mL, 0.138 mmol), BOP (18.29 mg, 0.041 mmol) and Et3N (0.019 mL, 0.138 mmol) in DMF (0.5 mL) was agitated at rt overnight. The reaction was complete by LC-MS, so the reaction was diluted to 1.5mL with methanol, then filtered and submitted for purification. This afforded 2-(3- ((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2- methoxyphenyl)-N,N-dimethylthiazole-5-carboxamide (1.9 mg, 3.70 umol, 13.41 % yield) LCMS m/z 499.5 (M+H)+; HPLC t K 0.72 min (analytical HPLC Method A); 1H NMR(500 MHz, DMSO-d6) 5 11.35 (s, 1H), 10.96 (s, 1H), 9.18 (s, 1H), 8.30 (s, 1H), 8.12 (br d, <7=8.1 Hz, 1H), 8.06 (s, 1H), 7.59 (br d, <7=7.7 Hz, 1H), 7.38 (t, <7=7.9 Hz, 1H), 3.80 (s, 3H), 3.53 - 3.40 (m, 3H), 3.25 (br s, 2H), 3.17 (br s, 1H), 3.04 (br s, 2H), 2.56 - 2.53 (m, 1H), 2.06 (br s, 1H), 0.86 - 0.77 (m, 4H) The Examples in Table 4 were prepared using a similar procedure used to prepare Example 239. Table 4 WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 240 D D 0 y־D Vnh N= n- J Vnh ,° ؟ 4 V h v 8 H 569.7 570.2 1.29QC- ACN- AA-XB 241q ם I , P * 629.7 630.3 1.36QC- ACN- TFA-XB 242 o> / *0 c =؟ 0 V' UC° O D D WNp ,N H HN N V^° 631.7 632.5 1.44QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 243 0 NN, N=/o x 0- ,495.6 496.2 0.99QC- ACN- TFA-XB 244 o o, z -z y —<' W V z ■ z . / = ' 15־ IZ o— z= v v 537.6 538.2 1.08QC- ACN- TFA-XB 245 oo z -z y —<1V zz7 ) = ' X5־ IZ o ^ > z=L 0 )^ " z ^ o 523.6 524.2 5.8 I 246 o> — o z -z y W / _ z1 / = / z7IZ ־ 1 o — z = ، M 481.5 482.1 5.8 I 247 0 ^-NH, N=/ 0 °' ° 564.7 565.2 4.4 I WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 248 D D 0yd Vnh N= n- ״׳ Vnh p X o H OH 558.6 559.2 1.11QC- ACN- AA-XB 249 HN Y׳ q ° O D 7,0 ח f ,N H HN N Y° 609.8 610.3 5.63 I 250 o "tn= O k q X z X z o— Z = Y T 2=0TZY aס ס 602.7 603.1 1.03QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 251 HO Y׳ UC° NH 0 D 7,0 ןז ] /U ,N H HN N Y° 596.7 597.3 1.37QC- ACN- AA-XB 252 D D 0. YD Vnh nY n- J >NH9 ■Vr 0 H I 569.7 570.1 1.12QC- ACN- AA-XB 253 c S^N T । 0 D 7,0 ןז ] YY^N'^O /L ,N H HN N Y° 554.6 555.3 1.35QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 254 D D 0 Vnh N=< n-״׳ >—NH P x 0' H 595.7 596.3 1.14QC- ACN- AA-XB 255 D D ox y-° Y—NH N=< n- m׳ >—NH P d h 542.6 543.4 1.29QC- ACN- AA-XB 256 / —N Y׳ uC° 0 D t،d ח f r^Tf'N'^D ,N H HN N Y° 512.6 513.4 1.06QC- ACN- TFA-XB 257 OH Y, uC° O D D /L ,N H HN N 'Y0 457.5 458.2 1.31QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 258 HO— Y1 UC° O D ,N H HN N 471.6 472.2 1.41QC- ACN- AA-XB 259 D D ox L0־ NH N= n — >—NH9 y«H 0^ o 0 1 556.7 557.1 1.77QC- ACN- AA-XB 260 nh2 S^N T । ^k/° LI 0 D ד,□ זז f r<:::Sr'N/^D /U ,N H HN N V^° 456.5 457.3 1.07QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 261 ם ם o 498.6 499.1 1.24QC- ACN- AA-XB 262 D D 0 ־ 0 y y—NH N= n — N' ))— NH °. ״ A M MAA o ° 512.6 513.3 1.06QC- ACN- TFA-XB 263 D D 0y-° y—NH N= n— J >—NH P A H MAA » Anh VT-s^yv 0 0 528.6 529.3 1.32QC- ACN- AA-XB 264 D D 0 y־D ——NH N=< n— MnH P 4V hOr J 523.6 524.2 1.3QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 265 y 0 NH Yl &° 0 D t,d ןז ] r^TA'N'^D /U ,N H HN N 534.6 535.4 1.07QC- ACN- TFA-XB 266 D D ox y־D NH N= n— NHP — < .׳ ، Av HV71 » y-NH U ^-v N^G. 0 0 514.6 515.4 1.42QC- ACN- AA-XB 267 HQ^ Y! UC° ^^NH 0 D 7,0 זז r N H , >؛• J HN N 485.6 486.5 0.73 A WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 268 z 7—z o — z = ( 1 / = o I Z ס ס 540.6 541.2 1.36QC- ACN- AA-XB 269 OH o =؟ 0 Y! &° ^NH 0 D 7,0 זז r /L ,N H HN N V^° 583.7 584.2 1.26QC- ACN- AA-XB 270ם ם „ S 484.6 485.1 1.38QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 271 D D 0 y—NH N= n—J NH ,° ° 0 528.6 529.4 1.38QC- ACN- AA-XB 272 ( NH Yl uc° 0 D f JL 1״D /L ,N H HN N 498.6 499.4 1.44QC- ACN- AA-XB 273 ^0 o =؟ 0 Y! UC° NH 0 D D r^YY^'N'^'D /L ,N H HN N V^° 588.7 589.1 1.33QC- ACN- AA-XB 274 0 hn'^ /NjQ NyN —N I N—، HN^q z o JL 579.7 580.2 0.86QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 275ם ס 7 = 0 568.7 569.3 1.64QC- ACN- AA-XB 276 X— 0=(^ Y! &° O D f JJ L.D YYnY X ,N H HN N xX 498.6 499.3 1.45QC- ACN- AA-XB 277 V/ /—N /= X N^S X^O^ XT F-^^NH O D D r^V^N^D X ,N H HN N xX 516.6 517.2 1.6QC- ACN- AA-XB 278 D P o YD NH N= n —m׳ >—NH P ST CKv-.- 0 514.6 515.2 1.23QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 279 ^0 HN Y &° 0 D rןז t,d N H HN N Y° 484.6 485.2 1.3QC- ACN- AA-XB 280 0•Z. HN ° Y uC° 0 D N H HN N Y° 520.6 521.2 1.18QC- ACN- TFA-XB 281 D D 0x YD y—NH N= n— N- >—NH9y mv,* 0 h 542.6 543.3 1.81QC- ACN- AA-XB 282 h2n Y׳ uC° ^^ NH 0 D D /L ,N H HN N Y60 442.5 443.2 0.98QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 283 / o y | 514.6 515.3 1.39QC- ACN- AA-XB 284 D P o y״D yNH N= n— N' >— NH0W’XL'6 H 509.6 510.2 1.33QC- ACN- AA-XB 285 =؟ 0 Y! &° O D Aw* HN N 497.6 498.3 1.36QC- ACN- AA-XB 286 b- =؟ o V' &° NH 0 D _ Aw* HN N 567.7 568.5 1.58QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 287 ° 1 X O T f X / / _ Z Z s __ J ---- / O 593.7 594.3 0.91QC- ACN- TFA-XB 288 d^d _° /? °X)j n ^yNH 579.7 580.3 0.9QC- ACN- TFA-XB 289 p NH =؟ 0 Yl a NH 0 D t,d ןז f r^V'^N'^D / L ,N H HN N V^o 560.7 561.2 1.56QC- ACN- TFA-XB 290 D D Xd /-NH N=/ 0 ،V_7 O—O 0 ،NH C-e 556.6 557.2 1.25QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 291 ) N — T 'U O D j Ld ך f . N H HN N ° Y 512.6 513.3 1.56QC- ACN- AA-XB 292 =؟ Q Y׳ U ^^NH O D r^Y^'N'^'D /، xN H HN N A 526.6 527.2 1.67QC- ACN- AA-XB 293 D DX-D ؟،/~NHN=Z° y NY/°~ OYNH595.7 596.3 1.36QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 294 6 =؟ o Y׳ U — NH 0 D f IT JD /L ״N H HN N 567.7 568.4 1.18QC- ACN- AA-XB 295 ם ם — O Z - < Z o 581.7 582.4 1.45QC- ACN- AA-XB 296 / o NH =؟ o Y! a O D /L ,N H HN N Y° 576.7 577.4 1.77QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 297 OH =؟ o Y!A0 NH 0 D D xN H HN N V^° 582.7 583.2 1.42QC- ACN- AA-XB 298 o o OCAR.
U =N HN—، ؟> d D D 586.7 587.2 1.92QC- ACN- AA-XB 299 D D°x X־D/-NH N=/ o N_NNHo- ° XnA 581.7 582.4 1.17QC- ACN- AA-XB 300 D D >^D /—NH N=V ״.-At,-- o 509.6 510.4 1.37QC- ACN- AA-XB 301/—NHN^Vo NH P~ 0 rAO-Z/'A0567.7 568.4 1.14QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 302 =ץ 0 Y! Q° 0 D fוז t,d xU ,N H HN N 554.6 555.4 1.41QC- ACN- AA-XB 303 ^NH =؟ 0 Y! U NH 0 D D D ' > ־^ N ־^' V ، ؛ > r .N H HN N A 512.6 513.3 1.57QC- ACN- AA-XB 304 D D /-NH N=Z 6m 555.6 556.3 1.21QC- ACN- AA-XB 305 D D °, X~D /—NH N=/ 1 ؟ /°~ 0 540.7 541.4 1.84QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 306 NH =؟ o Y׳ a ^^NH 0 D 7,0 זז ] Y^r'N'^o ,N H HN N 568.7 569.4 1.35QC- ACN- AA-XB 307 / —N NH V! Q° 0 D f IT 7,0 /L ,N H HN N 595.7 596.4 1.06QC- ACN- TFA-XB 308 ם ם 0 = 7 o 614.7 615.4 2.06QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 309 -^NH =؟ Q Y׳ U ^^NH 0 D D N^D /L ,N H HN N Y° 526.6 527.2 1.55QC- ACN- TFA-XB 310 ^ ־ v ^ o ^ Y y d ° Z ^ O ) / = o I Z א 526.6 527.2 1.7QC- ACN- AA-XB 311 D D°x Yd/—NHN=Vnyy~nY/°~ ° ° /־NH 541.6 542.1 1.16QC- ACN- AA-XB 312 ox NH U =؟ o S^N I I /Y/0 ( Y 0 D 7,0 ןז !י /L , N H HN N Y° 553.6 554.4 1.18QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 313 Yi &° O D 7,0 ח f ״N H HN N 510.6 511.3 1.46QC- ACN- AA-XB 314 ^ Z I 0 = 7 Y ו = d °rS ר « Z z ^ S 526.6 527.2 1.72QC- ACN- AA-XB 315 d =؟ 0 Y׳ U ^^NH O D WNp N H HN N v 581.7 582.2 1.1QC- ACN- AA-XB 316 D D °x YdYnH N=/ 0 Y^/~NYP~ 0 Ynh C-M 540.7 541.4 1.57QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 317 D D X-D /~NH N=/ 0 0 ،NH G- 555.7 556.2 1.11QC- ACN- AA-XB 318 I I &° ^^NH O D D ־^ N ׳^ r<،r Jl ',N H HN N 635.8 318.8 1.14QC- ACN- TFA-XB 319 NH | N ؟ a 0 D D r^^Y^N^D JL ',N h HN N 623.8 312.8 1.13QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 320 0=(^ S^N T । n O D D JL',n h HN N 538.6 539.3 1.76QC- ACN- AA-XB 321 D D o y־D Y—NHn־A n— N" V- NHP / N-=/ 5=( Nx ",nh 0 0 k^O 583.7 584.3 1.33QC- ACN- AA-XB 322 D D 0 y־D >—NH — n ־־، N V־NHP x ؛ w ° 0 *X/N^ 596.7 597.2 0.96QC- ACN- TFA-XB 323 ^NH / ^0 N— I I UC° O D rך jld JL',n h HN N V^° 581.7 582.4 1.37QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 324 D D0. y ־DY—NH ,°־־ y-NHV" n*o595.7 596.2 1.16QC- ACN- TFA-XB 325 Xo =؟ 0 Y׳ uC° ^-/NH 0 D D N H ؛ JlHN NA 596.7 597.1 1.75QC- ACN- AA-XB 326 p NH=؟ o Y׳uC°NH 0 D D JL <.n h HN N Y° 567.7 568.4 1.02QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 327 0 = 7 T l r ? a I ״ 579.7 580.4 1.05QC- ACN- TFA-XB 328 Y1 UC° 0 D D Np N H ؛ Jl HN N 524.6 525.3 1.59QC- ACN- AA-XB 329 NH =؟ 0 Y1 &° ^^NH 0 D D lY^Y^N^D Jl -,N H HN N 581.7 582.4 1.07QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 330 NH =؟ 0 Y׳ O D 0 - L זז f AYn^D JL ',n h HN N 581.7 582.2 1.09QC- ACN- TFA-XB 331 ox y—NH Cz° T । &° O D 7,0 זז f A >N H HN N xA 567.6 568.2 1.32QC- ACN- AA-XB 332 D D 0 A v-nh N־V n— N" VNH ° 0 42W.0N 0 o 611.7 612.4 1.24QC- ACN- AA-XB 333 D D 0 Y־D Y—NH nY n—J- —NH p Ox W—1,KN ° o 611.7 612.4 2.18QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 334 N— =؟ o V! &° 0 D rוז l.d r^^r'N'^D JL ',N h HN N 553.7 554.3 1.39QC- ACN- AA-XB 335 D D 0 /־D Y—NHnL n-N" V—NH 0 ° 0 583.7 584.4 1.08QC- ACN- TFA-XB 336 ^NH / ^0 N—( =؟ 0 S ^N T । ^x/° LI 0 D D JL ',N H HN N V^o 567.6 568.3 1.11QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 337 -Q NH =؟ O Y! UC° 0 D fח t,d Jl -,N H HN N A 567.7 568.3 1.04QC- ACN- TFA-XB 338 O ;־= __ x I Z x ס 593.7 594.4 1.16QC- ACN- AA-XB 339 D D 0 )^D NH N^، n- V- NH P V״ ° 0 583.7 584.4 1.09QC- ACN- TFA-XB 340 D D 0 y־D Vnh N^( n- N" ،NH / ° 0 581.7 582.4 1.18QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 341 D D Ox Y—NHnY n- I N" NH 0 IA,x 0 0 638.8 639.5 0.97QC- ACN- TFA-XB 342 OH =؟ o Y׳ &° O D 7,0 ח r AYn^D JL',n h HN N xA 666.8 667.3 1.16QC- ACN- AA-XB 343 =؟ 0 T । u ^-/NH 0 D JL JLJ8d JL>n h HN N xY° 609.8 610.1 1.07QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 344 n ' W ' °X/NH y— N >—N T H O'" S-& A—' X nYAAY > 11 r 7r N nJ ، J^Ynh o 607.8 608.4 1.32QC- ACN- AA-XB 345 =؟ Q Y׳ 63° 0 D fזז t,d AYn^d JL ',N H HN N xA 540.6 541.3 1.29QC- ACN- AA-XB 346 HO Y =؟ 0 63° 0 D f IT T,D jl >n h HN N A° 540.6 541.4 1.35QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 347 D DpY—NH,°־־ y-NH ^599.7 600.4 1.06QC- ACN- TFA-XB 348 D D 0 p Vnh y-NH ,°" !!! ° 0 638.8 639.3 1.17QC- ACN- AA-XB 349 D D < A —NH N־־{ n— ״״ NH p V' 595.7 596.4 1.29QC- ACN- AA-XB 350 0=^ I 1 a0 O D AJNp A -,N H HN N V^o 607.8 608.2 1.19QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 351 o y v A - O Z x > z O— V / I Z ס ס 621.8 622.4 1.08QC- ACN- TFA-XB 352 D D 0 A VNH n- N" -NH ° v? 0 0 569.7 570.1 1.06QC- ACN- TFA-XB 353 o ) = 0 I Z k a ס ס 596.7 597.2 1.34QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 354 ם ס ^ z x 0 = 7 T / = Z' — O Z - < Z o 595.7 596.2 1.25QC- ACN- AA-XB 355 D D D ^~ ؟ /-NH 0 0 /NH 595.7 596.3 1.14QC- ACN- TFA-XB 356 c N-' Y, U O D f IT L.D /k- ,N H HN N 554.6 555.2 1.51QC- ACN- AA-XB 357 z — Z I ° = 7 1 T Vl! T ך z 2 $ = ׳ 569.7 570.3 1.25QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 358 =؟ O Y! n° ^^NH 0 D rןז t,d /L ,N H HN N Y'° 524.6 525.4 1.28QC- ACN- TFA-XB 359 OH 0 d Y! Q° 0 D D X'<'D ־ N ؛،' Vx ، ؛ > r xN H HN N A 680.8 681.4 1.22QC- ACN- AA-XB 360q ם ° = ^ o 512.6 513.2 1.59QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 361 ץ =^ 0 Y׳ n° 0 D ד,□ זז r b -N H HN N 621.8 622.3 1.32QC- ACN- AA-XB 362 b - ׳ Y Q ° 0 D jd זז f yy^n^d . X ,N H HN N ° b 582.7 583.3 1.44QC- ACN- TFA-XB 363 ox Ynh D ץ I I a ^^־NH O D f JI L.D YY> 567.6 568.2 1.28QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 364ם ס 0 = 7 1 o 526.6 527.3 1.73QC- ACN- AA-XB 365 / —N NH =؟ O S T । /L/0 ( T O D D /L ,N H HN N V^° 609.8 610.4 1.02QC- ACN- TFA-XB 366 D D °, X־D /—NH N=/ o N^/ Nv_/O~ 0 J^NH <5 h 542.6 543.4 1.58QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 367 =؟ 0 Y׳ U O D f jj 7,0 N H HN N 0° 512.6 513.2 1.28QC- ACN- TFA-XB 368 NH ، =؟ O Y1 U 0 D 7,0 וז f r^V^N^D x-k ,N H HN N 0° 581.7 582.3 1.17QC- ACN- AA-XB 369 & 0 0 7,0 זז f /L ,N H HN N V^o 595.7 596.2 1.08QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 370 ( N— ץ =؟ O Y! n° 0 D rזז jdYSAn'B N H HN N 526.6 527.2 1.4QC- ACN- TFA-XB 371 o / V 4 - z' V z O— z = x 2 = 0 I Z ס ס 649.8 650.4 1.26QC- ACN- AA-XB 372 0 ؟, c =؟ Q Yl Q° O D /L ,N H HN N 602.7 603.2 1.23QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 373 D D 0 y—NH N= n— >—NH 445.5 446.4 1.19QC- ACN- AA-XB 374 o ) = o I Z x ־ ° ס ס 415.5 416.4 0.82QC- ACN- TFA-XB 375 D D ox —NH N= n— N- >—NH9 ° 498.6 499.4 0.65QC- ACN- TFA-XB 376 Q ox H2N O '—N O u __ (/ II I H " ، NY "؟ 0 S 440.5 441.2 1.01QC- ACN- AA-XB 377 0 /—NH, N=Z V>NH 0— O XN^ H,N C—A 496.6 497.3 0.74QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 378.Zr zL 1 1 Y ^ o I / =oIZ 481.6 482.2 0.79QC- ACN- AA-XB 379 Y! UC° ^־^NH 0 D 7,0 ןז f rAAN^D ,N H HN N /° 538.6 539.1 1.07QC- ACN- TFA-XB 380 V/ /—N /=( X nA Jx/O^ 0 D 7,0 זז f /L ,N H HN N * /° 556.6 557.1 1.57QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 381 o ZZ V - z o— z = ( /= oIZס ס 511.6 512.2 1.36QC- ACN- AA-XB 382 0 ؟״ o =؟ Q Y! uC° O D D /U ״N H HN N A 614.7 615.1 1.34QC- ACN- AA-XB 383 o ؟, o Y! UC° ^^NH 0 D D D ' > ־^ VX^'N ، ؛ > r /L ,N H HN N 612.7 613.2 1.25QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 384d ם 1 / = Z. — ° Z - < Zz 1 [ 3 o 522.6 523.3 1.3QC- ACN- AA-XB 385 HQ— Yl uc° O D 7,0 ץ f /U ,N H HN N nAN-N 484.6 485.2 1.34QC- ACN- AA-XB 386 OH Yl UC° ^^ NH 0 D 7,0 זז r /U ,N H HN N NA N-N 470.5 471.1 0.91QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 387 o^ NH Y! 3 0 D f JI 7,0 /L ,N H HN N /° 538.6 539.3 1.25QC- ACN- AA-XB 388 D D 0 y־D Vnh N= n- .° Vnh ״׳N_ V )=n ״ v v (~N°K 0 1 596.7 597.2 1.33QC- ACN- TFA-XB 389 nh2 Y! UC° 0 D D /L ,N H HN N /° 496.6 497.2 1.08QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 390 y° ° NH sYn T । LI O D X JI3^° /L ,N H HN N x° 574.7 575.1 1.35QC- ACN- AA-XB 391 D P 0yd >—NH N= n- ,° Vnh ׳ N x0 rUr tL0uY°x =/ 554.6 555.0 1.17QC- ACN- TFA-XB 392 HO— Y! uC° O D D INKp /L ,N H HN N 495.6 496.2 1.26QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 393 OH T1 UC ° 0 D t,d זז f ( A^n^d / L ,N H HN N 481.6 482.0 1.18QC- ACN- AA-XB 394 ( o Y, UC° 0 D r Jl3^° /L ,N H HN N 485.6 486.1 1.75QC- ACN- AA-XB 395 o 1 > ؛ — O z - z y M V z z / = 7 T 1 5 ־ I Z o - ^ Z = < r y A 586.7 587.0 1.48QC- ACN- AA-XB 396 I O^NH N 11 1^^ H । " // ' / 0 NH2 X__ ' 535.6 536.1 1.73QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 397 0. VnH2 Jk ^3-NH /0— Cj ° o 606.8 607.3 1.12QC- ACN- AA-XB 398 T O tn ^7 c p c h ,* ־ . D>— 4 z ־ z ° o 551.6 552.1 1.28QC- ACN- AA-XB 399 0. Vnh2 N= n- 0 ,° Vnh ״׳ vytyxc! 566.7 567.4 0.64QC- ACN- TFA-XB 400 I O^NH !ן N y ؛ Y"'YY H । H // a^k,u ° N- 0^ NH2 / OH 565.7 566.2 1.31QC- ACN- AA-XB 401 I O^NH A H । " // O/ NH2 / 509.6 510.3 1.35QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 402 X O^NH ^־ 11 N H । " // / 0 / NH2 0 , ' 8 , ----- ' 0 614.7 615.1 1.2QC- ACN- TFA-XB 403 o O . Z-Z V -- z = L w 521.6 522.3 1.55QC- ACN- AA-XB 404 0 = 7 1 Yc i l Iך 1 1 495.6 496.1 1.39QC- ACN- AA-XB 405o o, z -z y— <1 ^ v / _ zz Zz x5 ־ IZ z=L w z ^ o 578.7 579.2 1.27QC- ACN- AA-XB 406 0 ,N^ 0 NMNH2^״ A ؟ V H Ji" 0. CLs x nJ/ 410.5 411.3 1.39QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 407 I O^NH !ו N H । " // X o/ nh2 x 1 507.6 508.2 1.29QC- ACN- TFA-XB 408 / o Z I 0 = 7 « A O ’ Iר « z ׳z 4 x ° ^ 7 511.6 512.1 1.27QC- ACN- AA-XB Example409 N-(5-((2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)phenyl)amino)-6-methylpyridazin- -yl)cy cl oprop anecarb oxami de WO 2020/092196 PCT/US2019/058268 Step 1:A mixture of 4,6-dichloro-3-methylpyridazine (112 mg, 0.687 mmol), cyclopropanecarboxamide (64.3 mg, 0.756 mmol), C82CO3 (448 mg, 1.374 mmol), xantphos (59.6 mg, 0.103 mmol) and Pd2(dba)3 (62.9 mg, 0.069 mmol) in 1,4-Dioxane (mb) was placed in a microwave vessel, sparged with N2 for 5 minutes, sealed, and heated at 130 °C for 20 minutes. Cooled and filtered then purified by HPLC. HPLC conditions: Phenomenex Luna 5 micron C18 column (30 x 100mm); MeCN (0.1% TFA)/water (0.1% TFA); 10%-100% gradient over 15 minutes; 30 mL/min. Isolated product fractions and diluted with AcOEt (50 mL), which was washed with sat N8HCO3 (30 mL), dried over MgSO4 and concentrated under vacuo to give N-(5-chloro-6-methylpyridazin-3- yl)cyclopropanecarboxamide (35 mg, 0.165 mmol, 24.07 % yield). LCMS m/z 211.9/213.9 (M+H)+; HPLC 1r 0.72 min (analytical HPLC Method A); 1H NMR (400 MHz, CHLOROFORM-d) S 9.74 - 9.46 (m, 1H), 8.60 (s, 1H), 2.72 (s, 3H), 1.95 (tt, <7=7.9, 4.6 Hz, 1H), 1.22-1.10 (m, 2H), 1.03 - 0.92 (m, 2H).
Step 2:A mixture of N-(5-chloro-6-methylpyridazin-3-yl)cyclopropanecarboxamide (mg, 0.047 mmol), 2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3-yl)aniline (19.30 mg, 0.0mmol), Pd2(dba)3 (4.33 mg, 4.72 umol), xantphos (5.47 mg, 9.45 umol) and Cs2CO(46.2 mg, 0.142 mmol) in 1,4-Dioxane (1 mL) was sparged with N2 for 5 minutes. The reaction vessel was sealed and heated to 130 °C in a microwave for 30 min. Cooled and filtered then purified by HPLC to give N-(5-((2-methoxy-3-(l-methyl-lH-l,2,4-triazol-3- yl)phenyl)amino)-6-methylpyridazin-3-yl)cyclopropanecarboxamide (2.5 mg, 6.52 umol, 13.81 % yield). LCMS m/z 380.2 (M+H)+; HPLC 1r 1.00 min (analytical HPLC Method QC-ACN-AA-XB);1HNMR (500MHz, DMSO-d6) 5 10.85 (s, 1H), 8.54 (s, 1H), 7.90 (s, WO 2020/092196 PCT/US2019/058268 1H), 7.73 (d, 1=6.7 Hz, 1H), 131 - 7.31 (m, 2H), 7.29 - 7.23 (m, 1H), 3.93 (s, 3H), 2.(d, 1=3.1 Hz, 6H), 1.93 (br. s., 1H), 0.80 - 0.61 (m, 4H) Example 410 6-(cyclopropanecarboxamido)-4-((3-(5-(2-(dimethylamino)-2-oxoethyl)oxazol-2-yl)- 2-methoxyphenyl)amino)-/V-(methyl-d3)pyridazine-3-carboxamide Step 1:To a mixture of 3-((6-chloro-3-((methyl-d3)carbarnoyl)pyridazin-4-yl)amino)-2- methoxybenzoic acid (ref: Wipf, P. et at; Org. Lett., 2004,vol. 6, # 20, p. 3593 - 35(98 mg, 0.288 mmol) in dichloromethane (5 mL) and THF (5 mL)was added oxalyl WO 2020/092196 PCT/US2019/058268 chloride (0.050 mL, 0.577 mmol) and 1 drop of DMF. Stirred for one hour. Reaction mixture was concentrated in vacuo then dissolved in THF (5 mL). Ethyl 4- (bis(trimethylsilyl)amino)but-2-ynoate (102 mg, 0.375 mmol) and TBAF (0.288 mL, 0.288 mmol) were added. Stirred at rt overnight then quenched with water. The reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (24 g) using an EtOAc/Hex gradient (0-100% EtOAc over 13 CV) to give ethyl 4-(3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2- methoxybenzamido)but-2-ynoate (55 mg, 0.123 mmol, 42.5 % yield). 1H NMR (4MHz, CHLOROFORM-d) 5 11.10 (s, 1H), 8.28 (br s, 1H), 8.08 - 7.84 (m, 2H), 7.52 (dd, <7=7.9, 1.5 Hz, 1H), 7.35 (t, <7=7.9 Hz, 1H), 7.02 (s, 1H), 4.46 (d, <7=5.3 Hz, 2H), 4.26 (d, <7=7.3 Hz, 2H), 3.86 (s, 3H), 1.69 (br s, 3H), 1.33 (t, <7=7.0 Hz, 3H) Step 2:To a mixture of ethyl 4-(3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4- yl)amino)-2-methoxybenzamido)but-2-ynoate (55 mg, 0.123 mmol) in CH2Cl2 (5 mL) was added silica. The reaction was stirred at rt for 5 days. Reaction mixture was filtered washing well with 5%MeOH/DCM. Filtrate was concentrated. The crude material was purified on a silica gel cartridge (12 g) using an EtOAc/Hex gradient (0-100% EtOAc over 20 CV) to give ethyl 2-(2-(3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4- yl)amino)-2-methoxyphenyl)oxazol-5-yl)acetate (40 mg, 0.089 mmol, 72.7 % yield). LCMS m/z 449.1 (M+H)+; HPLC 1r 0.84 min (analytical HPLC Method B).
Step 3:A mixture of ethyl 2-(2-(3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4- yl)amino)-2-methoxyphenyl)oxazol-5-yl)acetate (40 mg, 0.089 mmol), cyclopropanecarboxamide (7.58 mg, 0.089 mmol), cesium carbonate (58.1 mg, 0.1mmol), xantphos (7.73 mg, 0.013 mmol) and Pd2(dba)3 (8.16 mg, 8.91 umol) in 1,4- Dioxane (2 mL) was placed in a microwave vessel, sparged with N2 for 5 minutes, sealed, and heated at 130 °C for 20 minutes. After cooling the reaction mixture was diluted with ethyl acetate and washed with sat NaCl. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (12 g) WO 2020/092196 PCT/US2019/058268 using an EtOAc/Hex gradient (0-100% EtOAc over 21 CV then held at 100% for 9CV) to give ethyl 2-(2-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4- yl)amino)-2-methoxyphenyl)oxazol-5-yl)acetate (31 mg, 0.062 mmol, 69.9 % yield).To a mixture of ethyl 2-(2-(3-((6-(cyclopropanecarboxamido)-3-((methyl- d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)oxazol-5-yl)acetate (31 mg, 0.0mmol) in THE was added IN NaOH (1 mL). Stirred at rt for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with sat KH2PO4. The organic layer was dried with MgSO4, filtered and concentrated to afford 2-(2-(3-((6- (cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2- methoxyphenyl)oxazol-5-yl)acetic acid (24 mg, 0.051 mmol, 84% yield). LCMS m/z 470.21 (M+H)+; HPLC 1r 0.69 min (analytical HPLC Method B).
Step 4:To a mixture of 2-(2-(3-((6-(cyclopropanecarboxamido)-3-((methyl- d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)oxazol-5-yl)acetic acid (24 mg, 0.051 mmol, 84%), dimethylamine hydrochloride (6.95 mg, 0.085 mmol), and BOP (11.31 mg, 0.026 mmol) in DMF (1 mL) was added Et3N (0.012 mL, 0.085 mmol). Stirred at rt for 1 hour. Filtered and purified by HPLC to give 6- (cyclopropanecarboxamido)-4-((3-(5-(2-(dimethylamino)-2-oxoethyl)oxazol-2-yl)-2- methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (3.7 mg, 7.30 umol, 42.9 % yield). LCMS m/z 497.2 (M+H)+; HPLC 1r 1.25 min (analytical HPLC Method QC-ACN-AA-XB);1H NMR in DMSO-d6 is consistent with desired product (500MHz, DMSO-d6) d 11.34 (s, 1H), 11.02 (s, 1H), 9.14 (s, 1H), 8.15 (s, 1H), 7.68 (d, 1=7.8 Hz, 1H), 7.60 (d, 1=7.8 Hz, 1H), 7.33 (t, 1=7.9 Hz, 1H), 7.18 (s, 1H), 3.97 (s, 2H), 3.73 (s, 3H), 3.08 (s, 3H), 2.86 (s, 3H), 2.07 (t, 1=5.2 Hz, 1H), 0.92 - 0.72 (m, 4H).
The Examples in Table 5 were prepared using a similar procedure used to prepare Example 410. Table 5 WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 411 d. P o y־D y—NH /0— Ap 2=01 1 VnH 0 H 526.6 527.4 0.95QC- ACN- TFA-XB 412 D D oK y-° y—NH n-N-Vnh /0— X VNH 0 H 579.7 580.2 1.04QC- ACN- AA-XB 413 o o z - z y— <1 V _ / / _ z z ־ י" /= ' z 1? I Z /O— Z = L O 465.5 466.4 1.14QC- ACN- AA-XB 414 I O^NH N 11 H । >'n O/ NH2 / 507.5 508.4 1.15QC- ACN- AA-XB 415 0 ^~nh N=/ 0 O- 0 Om 548.6 549.2 1.13QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 416 o o z - z y— <1 W ׳ V z z ) = ' X 1 5 ־ I Z /O — z = L p / - Z ^ O I 549.6 550.1 1.05QC- ACN- TFA-XB 417 o ov z - z y— <1 ' W V z / ) = / z 5 ־ I Z /O— z = L p / ^ Z ^ O r " ° 598.6 599.4 1.25QC- ACN- AA-XB 418 o o z - z y— <1 V - (/ _ z z z ) = ' X 5 ־ i z /O— z = L p o I 535.6 536.1 0.99QC- ACN- TFA-XB 419 I O^NH N 11 ^NAXr°x»0 r^K.vT ° N— 0^ NH2 / OH 521.5 522.2 1.11QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 420 0 z~nhN=Z° HZNH 0nRo 511.5 512.1 0.98QC- ACN- AA-XB 421 0 /—NH2 N=Z ،NH CnC 562.0 562.3 1.45QC- ACN- TFA-XB Example 422 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(l-(2-morpholinoethyl)-lH-l,2,3- triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide WO 2020/092196 PCT/US2019/058268 TMS Step 1:To a solution of 2-bromo-6-nitrophenol (5 g, 22.94 mmol) in DMF (18 ml) was added potassium carbonate (9.51 g, 68.8 mmol). The resulting mixture was stirred for 15minutes, then iodomethane (2.87 ml, 45.9 mmol) was added. The resulting mixture was stirred at room temperature overnight.HPLC and LC-MS indicated complete conversion to product. Cold water was added (75 mL), and the resulting mixture was stirred and sonicated. Next, the solid was collected with filtration.This material was then dissolved in EtOAc (150mL). Thissolution was washed lx with 10% LiCl and lx with brine. The reaction mixture was dried over sodium sulfate, then filtered and concentrated. This was loaded onto a 120g ISCO column, then purified by flash chromatography eluting with 0-50% EtOAc in hexanes. The reaction afforded a pale yellow solid, l-bromo-2-methoxy-3-nitrobenzene (4.997 g, 20.46 mmol, 89 % yield) HPLC /r 0.92 min (analytical HPLC Method A).Step 2:A mixture of l-bromo-2-methoxy-3-nitrobenzene (2.48 g, 9.62 mmol), zinc (6.g, 96 mmol) and ammonium chloride (5.15 g, 96 mmol) in ethanol (40 mL) and water WO 2020/092196 PCT/US2019/058268 (5.71 mL) was stirred at room temperature overnight. The reaction was then diluted with di chloromethane (200 ml), and filtered. The filtrate was washed with water (50 ml), dried (Na2SO4), and concentrated. Redissolved this material in DCM, and loaded onto a 80g colmn for purification by flash chromatography, eluting with 0-100% EtOAc in hexanes. The reaction afforded 3-bromo-2-m ethoxyaniline (1.95 g, 9.17 mmol, 95 % yield) as a colorless oil.HPLC Zr 0.77 min (analytical HPLC Method A).
Step 3:A mixture of 3-bromo-2-methoxyaniline (1.0 g, 4.95 mmol), Bis(triphenylphosphine)palladium(II) chloride (0.347 g, 0.495 mmol), and Copper(I) iodide (0.377 g, 1.980 mmol) in DMA (20 mL) was stirred at room temperature and degassed by bubbling dry nitrogen through it for 10 minutes. Then ethynyltrimethylsilane (3.50 mL, 24.75 mmol) and diisopropylamine (15.41 mL, 109 mmol) were added and the reaction mixture immediately became a yellow solution. The pressure vessel was then sealed and placed into a warm 105 °C bath. Stirred at 105 °C overnight.The diisopropylamine was evaporated and the excess TMS-acetylene, then diluted with 100mL ethyl acetate. The organic solution was washed with lx 1:1 ammonium hydroxide :sat. ammonium chloride, lx sat. ammonium chloride, lx 10% aq. LiCl, lx brine and dried over sodium sulfate. This was then filtered and concentrated, and loaded onto a 80g ISCO column for purification by flash chromatography eluting with 0-100% EtOAc in hexanes to afforded 2-methoxy-3-((trimethylsilyl)ethynyl)aniline (995 mg, 2.mmol, 59.6 % yield) as an impure brown solid. Carried on as-is to deprotection. LCMS m/z 220.2 (M+H)+; HPLC fe 0.94 min (analytical HPLC Method A).
Step 4:A mixture of 2-methoxy-3-((trimethylsilyl)ethynyl)aniline (995 mg, 4.54 mmol) and potassium carbonate (1881 mg, 13.61 mmol) in methanol (15 mL) was stirred at room temperature for 30 minutes. After 30 minutes, the reaction was complete. Partitioned between EtOAc (50mL) and water (25mL). The aqueous layer was washed with lx EtOAc, then washed combined EtOAc layer lx saturated ammonium chloride, WO 2020/092196 PCT/US2019/058268 x brine. The reaction mixture was dried over sodium sulfate, then filtered and concentrated. The oil was loaded onto a 12g ISCO column, then purified by flash chromatography, eluting with 0-10% MeOH in DCM to afford 3-ethynyl-2- methoxyaniline (301 mg, 2.004 mmol, 44.2 % yield) as an orange oil. HPLC /r 0.52 min (analytical HPLC Method A).
Step 5:4,6-dichloro-A-(methyl-d3)pyridazine-3-carboxamide (220 mg, 1.052 mmol) was dissolved in Tetrahydrofuran (6 mL) and 3-ethynyl-2-methoxyaniline (163 mg, 1.1mmol) was added. To this solution was added lithium bis(trimethylsilyl)amide (2.63 mL, 2.63 mmol) in a dropwise manner (<2 min) using a needle and syringe and the reaction stirred until complete by LCMS (~15 min). HC1 (IM aq) (1.579 mL, 1.579 mmol) was added to quench the residual base. Then the reaction was partitioned between EtOAc and water. The water layer was washed lx ethyl acetate, and then the combined organic layer was washed lx ammonium chloride (sat.), lx brine. It was then dried over sdoium sulfate, then filtered and concentrated to afford the crude acetylene as a tan solid. The reaction mixture was redissolved in DCM, then loaded onto a 24g ISCO column for purification by flash chromatography eluting with 0-100% EtOAc in hexanes. The reaction afforded 6-chloro-4-((3-ethynyl-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3- carboxamide (228 mg, 0.677 mmol, 64.4 % yield) as a white solid. LCMS m/z 320.(M+H)+; HPLC fe 0.90 min (analytical HPLC Method A).
Step 6:Benzoic acid (2 mg, 0.016 mmol), L-Ascorbic acid sodium salt (2 mg, 10.umol), and Copper(II) sulfate (2 mg, 0.013 mmol) were all weighed into the small flask containing 6-chloro-4-((3 -ethynyl-2-methoxyphenyl)amino)-A-(methyl-d3)pyridazine-3 - carboxamide (77 mg, 0.241 mmol) . A solution of 4-(2-azidoethyl)morpholine (75 mg, 0.482 mmol)in t-BuOH (1.5 mL) and Water (1.5 mL) was added and the mixture was stirred at room temperature. After stirring overnight, the reaction was complete. Diluted WO 2020/092196 PCT/US2019/058268 with EtOAc (50mL) and 10mL water. Washed organic layer lx brine, then dried over sodium sulfate, filtered and concentrated. Loaded onto a 12g column, purified by flash chromatography eluting with 0-100% EtOAc in hexanes. The reaction afforded 6-chloro- 4-((2-methoxy-3-(l-(2-morpholinoethyl)-lH-l,2,3-triazol-4-yl)phenyl)amino)-A- trideuteromethylpyridazine-3-carboxamide (108 mg, 0.216 mmol, 90 % yield), a colorless oil. LCMS m/z 476.4 (M+H)+; HPLC t K 0.62 min (analytical HPLC Method A).
Step 7:A mixture of 6-chloro-4-((2-methoxy-3-(l-(2-morpholinoethyl)- 1H-1,2,3-triazol- 4-yl)phenyl)amino)-A-trideuteromethylpyridazine-3-carboxamide (26 mg, 0.055 mmol), Xantphos (6.32 mg, 10.93 umol), and cyclopropanecarboxamide (9.30 mg, 0.109 mmol) in dioxane (1mL) was degassed by bubbling N2 through it for 5 minutes. Then C82CO(71.2 mg, 0.219 mmol) and Pd2(dba)3 (5.00 mg, 5.46 umol) were added. Then the vessel was sealed, and the reaction was stirred at 120 °C for 2h. The reaction was complete by LC-MS. Diluted with DMF, filtered and submitted for purification. The reaction afforded 6-(cyclopropanecarboxamido)-4-((2-m ethoxy-3-(l -(2-morpholinoethyl)-1H- 1,2,3-triazol- 4-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide (15.3 mg, 0.029 mmol, 52.3 % yield). LCMS m/z 525.5 (M+H)+; HPLC 1r 0.58 min (analytical HPLC Method A); 1H NMR (500MHz, DMSO-d6)8 11.33 (s, 1H), 10.98 (s, 1H), 9.16 (s, 1H), 8.50 (s, 1H), 8.13 (s, 1H), 7.95 (d, 1=8.1 Hz, 1H), 7.43 (d, 1=7.4 Hz, 1H), 7.34 - 7.28 (m, 1H), 4.59 (t, 1=5.7 Hz, 2H), 3.66 (s, 3H), 3.54 (br. s., 2H), 2.90 (s, 1H), 2.82 (br. s., 1H), 2.(s, 1H), 2.46 (br. s., 3H), 2.11 - 2.04 (m, 1H), 0.85 - 0.79 (m, 4H) The Examples in Table 6 were prepared using a similar procedure used to prepare Example 422.
Table 6 WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 423 D D /~NH N=/ 0 0- H ?~NH 526.6 527.2 1.21QC- ACN- AA-XB 424 0^ ،N N-N & 0 D 7,0 זז r -N H HN N 548.6 549.4 1.32QC- ACN- AA-XB 425 o-X ،N N-N & ^^ NH 0 D D Y^N'^<'D ، ؛؛ > r /L ,N H HN N r^N k_ I| HO" 591.7 592.3 1.3QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Example 426 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-(2-((2-methoxyethyl)amino)-2- oxoethyl)-2H-l,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3- carboxamide Br/Ox/Lx Step-1JL S * /-°xh2n'^/h2n/ Step-2 HN-N Step-3Br —^/NBr 4) 0 cN-N + D3C^ 1 JY H L 00h2n׳׳^^ J rO VO Step-8״ D3C°״ 8 N ، V / ,ס OxB pXx °XH 1 Step-4 / step-5, ------------- ► N—N r( Br^V N 4S ؟N-N HjN^^N ^؛׳ BrBr 4CnStep-6 Y step-7 1" 06 —HN^/D3C-nAAH LX N Cl o OH ___/ NH y 0 ‘ 0 06 — ״Xft T O HN —^n־^SO>1 0 JL Js.h 1 | 3 וו n v ^ 0 !ךHo WO 2020/092196 PCT/US2019/058268 Step 1:A solution of 3-bromo-2-methoxyaniline (0.95 g, 4.70 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.791 g, 7.05 mmol),PdC12(dppf)- CH2C12Adduct (0.192 g, 0.235 mmol) and potassium acetate (1.384 g, 14.11 mmol) in Dioxane (20 mL) in a flask was heated to reflux overnight. Cooled to room temperature, concentrated in vacuo on Celite. This crude product was purified by flash chromatography using an ISCO 80g column (solid loading) eluting with 0-50% EA/hex. Appropriate fractions (25% EtOAc) were collected and concentrated in vacuo to give 2- methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.96 g, 3.78 mmol, 80 % yield) as an off-white solid. LCMS m/z 250.0 (M+H)+; HPLC /r 0.70 min (analytical HPLC Method A).
Step 2:To a solution of H-1,2,3-triazole (0.524 mL, 9.05 mmol) in water (5 mL) at °C was added bromine (0.625 mL, 12.13 mmol). The reaction was stirred at 50 °C for minutes, whereupon the precipitated product was filtered off. This material was air-dried on the filter. Another aliquot of bromine (0.625 mL, 12.13 mmol) was added to the mother liquor, which was stirred at room temperature overnight. After stirring overnight, collected the solid product by filtration. Filtered off a total of 4,5-dibromo-l/M,2,3- triazole (1.83 g, 7.91 mmol, 87 % yield) as a white solid. Carried on as-is to alkylation.
Step 3: WO 2020/092196 PCT/US2019/058268 To a solution of 4,5-dibromo-lH-l,2,3-triazole (1.5 g, 6.61 mmol) in DMF (mL) at -10 °C (in an salt-ice-water bath) was added first potassium carbonate (1.828 g, 13.22 mmol). After stirring 15 minutes, ethyl bromoacetate (0.736 mL, 6.61 mmol) was added dropwise. After Ih, LC-MS indicated that the reaction is complete. The reaction mixture was quenched with 10mL water and extracted 4x with 50mL EtOAc. The reaction mixture was washed with combined EtOac lx 10% LiCl, lx brine and dried over sodium sulfate, filtered and concentrated. The reaction mixture was loaded onto a 40g ISCO column for purification by flash chromatography, eluting with 0-100% EtOAc in hexanes. The reaction afforded ethyl 2-(4,5-dibromo-2/7-l,2,3-triazol-2-yl)acetate (1.4g, 4.67 mmol, 70.6 % yield). Very little of the other isomer observed, none isolated. . LCMS m/z 313.9 / 315.9 (M+H)+; HPLC t K 1.00 min (analytical HPLC Method A). 1H NMR (400MHz, CHLOROFORM-d) 5 5.14 (s, 2H), 4.26 (q, 1=7.2 Hz, 2H), 1.29 (t, 1=7.2 Hz, 3H) Step 4:A stirred mixture of ethyl 2-(4,5-dibromo-2/7-l,2,3-triazol-2-yl)acetate (1.1 g, 3.51 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.876 g, 3.51 mmol) and PdC12(dppf)-CH2C12Adduct (0.100 g, 0.123 mmol)in Dioxane (35 mL) was degassed by bubbling nitrogen through the mixture for 5 minutes. 2M K3PO4 (aq) (5.27 mL, 10.54 mmol) was quickly added and the reaction mixture heated at 50 °C for minutes. The reaction turned dark almost immediately. LC-MS showed complete consumption of the starting material. The reaction mixture was cooled to room temperature, then diluted with EtOAc (75mL). This solution was then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography, eluting with 0-100% EtOAc in hexanes. The reaction afforded ethyl 2-(4-(3-amino-2-methoxyphenyl)-5- bromo-2/7-l,2,3-triazol-2-yl)acetate (0.595 g, 1.642 mmol, 46.7 % yield) as a tan solid. LCMS m/z 355.1 / 357.1 (M+H)+; HPLC 1r 0.98 min (analytical HPLC Method A).
Step 5:Ethyl 2-(4-(3-amino-2-methoxyphenyl)-5-bromo-2/7-l,2,3-triazol-2-yl)acetate (0.595 g, 1.675 mmol) was dissolved in Ethanol (12 mL), and 10% Pd on C (0.446 g, 0.419 mmol) was added. This mixture was degassed, and then flooded with hydrogen gas.
WO 2020/092196 PCT/US2019/058268 This was stirred at 50 °C overnight. After stirring overnight, the reaction is complete. Diluted with EtOAc /MeOH, then filtered through Celite and concnetrated to afford ethyl 2-(4-(3-amino-2-methoxyphenyl)-2/M,2,3-triazol-2-yl)acetate, AcOH (0.575 g, 1.6mmol, 97 % yield) as a tan solid. LCMS m/z 277.1 (M+H)+; HPLC /r 0.72 min (analytical HPLC Method A); 1H NMR (400MHz, METHANOL-d4) 5 8.12 (s, 1H), 7.19 (dd, 1=7.7, 1.6 Hz, 1H), 6.96 (t, 1=7.8 Hz, 1H), 6.84 (dd, 1=7.9, 1.6 Hz, 1H), 5.36 (s, 2H), 4.27 (q, 1=7.1 Hz, 2H), 3.68 (s, 3H), 1.30 (t, 1=7.1 Hz, 3H) Step 6:To a solution of 4,6-dichloro-A-(methyl-d3)pyridazine-3-carboxamide (155 mg, 0.741 mmol) and ethyl 2-(4-(3-amino-2-methoxyphenyl)-2/M,2,3-triazol-2-yl)acetate, AcOH (262 mg, 0.779 mmol) in Tetrahydrofuran (6 mL)was added lithium bis(trimethylsilyl)amide (2.224 mL, 2.224 mmol) in a dropwise manner (<1 min) using a syringe and the reaction stirred until complete by LCMS (~15 min). HC1 (IM aq) (0.2mL, 1.112 mmol) was added to quench the residual base. Then the reaction was partitioned between EtOAc and water. The water layer was washed lx ethyl acetate, and then the combined organic layer was washed lx ammonium chloride (sat.), lx brine. It was then dried over sdoium sulfate, then filtered and concentrated to afford the crude acetylene as a tan solid. Redissolved in DCM, then loaded onto a 12g ISCO column for purification by flash chromatography. Eluted with 0-100% EtOAc in hexanes. The reaction afforded ethyl 2-(4-(3-((6-chl oro-3-(trideuteromethylcarbamoyl)pyridazin-4- yl)amino)-2-methoxyphenyl)-2/M,2,3-triazol-2-yl)acetate (135 mg, 0.298 mmol, 40.2 % yield) as an off-white solid. LCMS m/z 449.3 (M+H)+; HPLC /r 0.91 min (analytical HPLC Method A).
Step 7:A mixture of ethyl 2-(4-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4- yl)amino)-2-methoxyphenyl)-2/M,2,3-triazol-2-yl)acetate (120 mg, 0.267 mmol), Xantphos (30.9 mg, 0.053 mmol), and cyclopropanecarboxamide (45.5 mg, 0.535 mmol) in dioxane (3 mL) was degassed by bubbling N2 through it for 5 minutes. Then C82CO(348 mg, 1.069 mmol) and Pd2(dba)3 (24.48 mg, 0.027 mmol) were added, the vessel was sealed, and the reaction was stirred at 120 °C for 90 minutes. The reaction was complete WO 2020/092196 PCT/US2019/058268 by LC-MS, so the crude material was concentrated onto Celite and purified by flash chromatography, using a 24g ISCO column and eluting with 0-100% EtOAc in hexanes to afford ethyl 2-(4-(3-((6-(cyclopropanecarboxamido)-3-((methyl- d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-2//-l,2,3-triazol-2-yl)acetate (mg, 0.120 mmol, 44.9 % yield). LCMS m/z 498.4 (M+H)+; HPLC Zr 0.79 min (analytical HPLC Method A).
Step 8:To a solution of ethyl 2-(4-(3-((6-(cyclopropanecarboxamido)-3-((methyl- d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-2/Z-l,2,3-triazol-2-yl)acetate (mg, 0.123 mmol) in Tetrahydrofuran (1 mL) was added INNaOH (0.135 mL, 0.1mmol) and a few drops of methanol. The solution was stirred at room temperature. After 2h, the reaction is complete. Neutralised with 140uL IN HC1, then diluted with 50mL EtOAc. Dried this mixture over sodium sulfate, then filtered and concentrated to afford crude 2-(4-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4- yl)amino)-2-methoxyphenyl)-2//-l,2,3-triazol-2-yl)acetic acid (56 mg, 0.113 mmol, 92 % yield) as a yellow solid. LCMS m/z 470.2 (M+H)+; HPLC Zr 0.67 min (analytical HPLC Method A).
Step 9:A solution of 2-(4-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethyl carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-2//-l,2,3-triazol-2-yl)acetic acid (mg, 0.064 mmol) , BOP (42.4 mg, 0.096 mmol) , 2-methoxyethanamine (14.40 mg, 0.1mmol), and DIEA (0.056 mL, 0.320 mmol) in DMF (1 mL) was stirred for 45 minutes at room temperature. The reaction appears to be complete by LC-MS.. The reaction mixture was diluted with DMF, then filtered and purified by prep HPLC to afford 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(2-(2-((2-methoxyethyl)amino)-2- oxoethyl )-27/-1,2,3-tri azol-4-yl )phenyl )amino)-N-trideuteromethylpyridazine-3- carboxamide (10.6 mg, 0.020 mmol, 30.6 % yield) LCMS m/z 527.3 (M+H)+; HPLC Zr 0.67 min (analytical HPLC Method A).
WO 2020/092196 PCT/US2019/058268 The Examples in Table 7 were prepared using a similar procedure used to prepare Example 426. Table 7 Ex.No.Structure MWObs. MS IonRTQC Method 427 D D 0. rD —NH ^nn zO— ؟ 1 >NH 0 H 496.5 497.3 1.42QC- ACN- AA-XB 428 D D 0 y—NH NH /°— ؟ 3 >^nh 0 H L 552.7 553.2 1.53QC- ACN- TFA-XB 429 D D o A y—NH NH Z°' <3 ? yNH 0 H 512.5 513.2 0.89QC- ACN- TFA-XB 430 D D ox A y—NH 1//)—NH /0— V nv-C" 1 V NH X o H 553.6 554.4 1.6QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 431 D D 0 ^־D y—NH N= n— 4 }=_/N uV ^NH Vn'N^N^O^ 0 H 554.6 555.3 1.77QC- ACN- AA-XB 432 Dx P o y־D y—NH N'N y^NH /O— <3yT o —NH o' H 496.5 497.3 1.27QC- ACN- AA-XB 433 D D Ox y־D y—NH N= n— . N ^NH ? 0 >ן ^NH Vn'^N^A 0 H 526.6 527.3 1.14QC- ACN- TFA-XB 434 D P 0 y״D Y—NH n^/^nh /0' 4v y-c^ °" /Vnh V n'n^nA6 H 0 532.6 533.3 1.36QC- ACN- AA-XB 435 D D ox )^D y— nh N= n— 9 NH — < ״׳ 4 H HL-T"h »n yNH V/ 0 H 521.6 522.3 1.31QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 436 D D 0 4° y—NH 4 H )—N ^NH 531.6532.24,1.18QC- ACN- AA-XB 437 ־^ 0 4 ^ ־ » L z M ^ = ° 547.6 548.2 1.38QC- ACN- AA-XB 438 D P o y־D y—NH N= n— ,° NH < ،.׳ 4.Ny-^ 0 O4 —NH 0 H 566.6 567.3 1.3QC- ACN- AA-XB 439 D D ox4d —NH . Nn^ NH 4؟ 4/4 y-^ yV^nh o' H 495.6 496.1 1.1QC- ACN- AA-XB 440 D D 0.4d Y—NH n/=4— NHp״H ?"Vr" h »n yNH V_y 0 H 520.6 521.2 1.14QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 441 D D 0yd y—NH ؟ ^ 3 Y > Ynh V/ 0 H 525.6 526.1 1.18QC- ACN- AA-XB 442 h2n N-N v, Y 0 D HN/^N/ Y 453.5 454.4 0.94QC- ACN- AA-XB 443 D D o. z° y—NH <3 }=/N H Ynh U^n'n^nY6 H BOH 539.6 540.3 1.14QC- ACN- AA-XB 444 O Ynh2 0 V^T/0' H Ynh 445 / O Y 508.5 509.2 1.16QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 446 o ^-nh2 0 H J^NH ny^m 447 L z " ؟ J 7 ° o T 512.5 513.2 1.16QC- ACN- AA-XB 448 h2n N-N X1 0 D D ،X• ,N H HN N 454.5 455.2 0.99QC- ACN- AA-XB 449 °^ N r N-N & ^^NH 0 D 7,0 זז r ,N H HN N ،،° 538.6 539.2 1.09QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 450 ho^ N-N x، 0 D f IT 7,0 /k■ ,N H HN N 455.5 456.3 1.25QC- ACN- AA-XB Example 451 4-((2-methoxy-3-(2-methyl-2H-l,2,3-triazol-4-yl)phenyl)amino)-6-((6- methoxypyridazin-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide WO 2020/092196 PCT/US2019/058268 Step-1Step-2 Step-3+ D,CXNHStep-4 Step 1:To a solution of 4,5-dibromo-l/M,2,3-triazole (0.401 g, 1.768 mmol) in DMF (6mL) at 0 °C (in an ice-water bath) was added first potassium carbonate (0.366 g, 2.mmol) and then iodomethane (0.116 mL, 1.856 mmol) was added dropwise.After stirring Ih, the reaction appears to be incomplete by HPLC. Added additional 50uL iodomethane, continued stirring, now at room temp. Reaction still appears to incomplete. Added additional 50uL iodomethane. Quenched with 10mL water. Extracted 2x 50mLEtOAc. Washed combined EtOac lx 10% LiCl, lx brine.Then dried over sodium suflate, filtered and concentrated. Loaded onto a 40g ISCO column for purification by flash chromatography, eluting with 0-100% EtOAc in hexanes. Two peaks elute, the first eluting being larger by UV absorbance, but giving no MS signal. This is 4,5-dibromo-2- methyl -2/7-1,2,3-triazole (0.266 g, 1.082 mmol, 61.2 % yield), designated Isomer 2.HPLC fe 0.90 min (analytical HPLC Method A^H NMR (400MHz, chloroform-d) 4.17 (s, 3H). The second peak is smaller by UV, but gives the correct mass and dibromo isotopic pattern in MS. This material is 4,5-dibromo-2-methyl-2J/-l,2,3-triazole (0.101 g, 1.082 mmol, 61.2 % yield) designated Isomer 1. LCMS m/z 242.0 / 244.0 (M+H)+; HPLC WO 2020/092196 PCT/US2019/058268 /r 0.67 min (analytical HPLC Method A). 1H NMR (400MHz, chloroform-d) 5 4.08 (s, 3H) Step 2:A stirred mixture of 4,5-dibromo-2-methyl-2/7-l,2,3-triazole (100 mg, 0.4mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (98 mg, 0.3mmol) and PdC12(dppf)-CH2C12Adduct (16.95 mg, 0.021 mmol)in Dioxane (3 mL) was degassed by bubbling nitrogen through the mixture for 5 minutes. 2M K3PO4 (aq) (0.6mL, 1.245 mmol) was quickly added and the reaction mixture heated at 50 °C for minutes. The reaction turned dark almost immediately even at this lower temperature. LC-MS showed complete consumption of the starting material. The reaction mixture was cooled to room temperature, then diluted with EtOAc (75mL). This solution was then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography, eluting with 0-100% EtOAc in hexanes. The reaction afforded 3-(5-bromo-2-methyl-2/7- 1,2,3-triazol-4-yl)-2-methoxyaniline (70 mg, 0.247 mmol, 59.6 % yield) as a yellow oil. LCMS m/z 283.1 /285.1 (M+H)+; HPLC fe 1.11 min (analytical HPLC Method A).
Step 3:3-(5-bromo-2-methyl-2//-l,2,3-triazol-4-yl)-2-methoxyaniline (0.145 g, 0.5mmol) was dissolved in Ethyl acetate (5 mL), and 10% Pd on C (0.136 g, 0.128 mmol) was added. This mixture was degassed, and then flooded with hydrogen gas. This was stirred overnight at room temperature. After stirring overnight, LC-Ms indicates a clean reaction with -30% conversion to desired product. Added additional 10% Pd on C (0.1g, 0.128 mmol) and Ethanol (1 mL). This mixture was re-degassed, and then flooded with hydrogen gas. This was stirred at 50 °C for 3h. After 3h, the reaction is complete. Filtered and concnetrated to afford 2-methoxy-3-(2-methyl-2/7-l,2,3-triazol-4-yl)aniline (78 mg, 0.374 mmol, 73.1 % yield) as a tan solid. LCMS m/z 205.1 (M+H)+; HPLC /r 0.70 min (analytical HPLC Method A).
Step 4:To a solution of 4,6-dichloro-A-(methyl-d3)pyridazine-3-carboxamide (270 mg, 1.292 mmol) and 2-methoxy-3-(2-methyl-2/7-l,2,3-triazol-4-yl)aniline (290 mg, 1.4 WO 2020/092196 PCT/US2019/058268 mmol) in Tetrahydrofuran (10 mL)was added lithium bis(trimethylsilyl)amide (3.23 mL, 3.23 mmol) in a dropwise manner (<5 min) using a syringe and the reaction stirred until complete by LCMS (~15 min). HC1 (IM aq) (0.484 mL, 1.937 mmol) was added to quench the residual base. Then the reaction was partitioned between EtOAc and water. The water layer was washed lx ethyl acetate, and then the combined organic layer was washed lx ammonium chloride (sat.), lx brine. It was then dried over sdoium sulfate, then filtered and concentrated to afford the crude acetylene as a tan solid. Redissolved in DCM, then loaded onto a 24g ISCO column for purification by flash chromatography. Eluted with 0-100% EtOAc in hexanes. The reaction afforded 6-chloro-4-((2-methoxy-3- (2-methyl-2H-l,2,3-triazol-4-yl)phenyl)amino)-A-trideuteromethylpyridazine-3- carboxamide (182 mg, 0.473 mmol, 36.6 % yield) as an off-white solid. LCMS m/z 377.(M+H)+; HPLC t K 0.87 min (analytical HPLC Method A).
Step 5:A mixture of 6-chloro-4-((2-methoxy-3-(2-methyl-27/- 1,2,3-triazol -4- yl)phenyl)amino)-A-trideuteromethylpyridazine-3-carboxamide (30 mg, 0.080 mmol), Xantphos (9.21 mg, 0.016 mmol), and 6-methoxypyridazin-3-amine (19.92 mg, 0.1mmol) in dioxane (1.5 mL) was degassed by bubbling N2 through it for 5 minutes. Then C82CO3 (104 mg, 0.318 mmol) and Pd2(dba)3 (7.29 mg, 7.96 umol) were added, the vessel was sealed, and the reaction was stirred at 130 °C for 45 minutes. The reaction was complete by LC-MS. The reaction was cooled to room temperature, and then was diluted with DMF. This solution was then filtered and purified by prep HPLC. The reaction afforded 4-((2-methoxy-3-(2-methyl-2//-l,2,3-triazol-4-yl)phenyl)amino)-6-((6- methoxypyridazin-3-yl)amino)-A-trideuteromethylpyridazine-3-carboxamide (22 mg, 0.046 mmol, 58.2 % yield) as a yellow solid. LCMS m/z 466.2 (M+H)+; HPLC /r 0.min (analytical HPLC Method A);1H NMR (400MHz, DMSO-d6) 5 11.05 (s, 1H), 10.27 (s, 1H), 9.14 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.93 (d, 1=9.5 Hz, 1H), 7.68 (dd, 1=7.9, 1.5 Hz, 1H), 7.57 (dd, 1=8.0, 1.4 Hz, 1H), 7.30 (t, 1=7.9 Hz, 1H), 7.22 (d, 1=9.5 Hz, 1H), 4.24 (s, 3H), 3.95 (s, 3H), 3.68 (s, 3H) WO 2020/092196 PCT/US2019/058268 The Examples in Table 8 were prepared using a similar procedure used to prepareExample 451. Table 8 Ex.No.Structure MWObs. MS IonRTQC Method 452 ^0 hn^n 0 D LI y'x/" N, /? N-N 482.5 483.2 1.57QC- ACN- AA-XB 453 -N nY J,O^ H F'^^NH 0 D HN N Y:° 442.5 443.2 1.57QC- ACN- AA-XB 454 -N Y^o^ LT O D A** HN N Y'n Lu H0Y 509.6 510.1 1.59QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Example 455 6-(cyclopropanecarboxamido)-4-((3-(5-(l,l-dioxidothiomorpholine-4-carbonyl)-l- methyl-lH-pyrazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3- carboxamide Step 1:A stirred mixture of methyl 3-chloro-l-methyl-l//-pyrazole-5-carboxylate (200mg, 1.146 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (4mg, 2.005 mmol) and l,l'-bis(di-tert-butylphosphino)ferrocene palladium di chloride WO 2020/092196 PCT/US2019/058268 (37.3 mg, 0.057 mmol) in Dioxane (6 ml) was degassed by bubbling nitrogen through the mixture for 5 minutes. 2M K3PO4 (aq) (1.718 ml, 3.44 mmol) was quickly added and the reaction mixture heated at 125 °C for 1 hr. The reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was washed with brine (30 ml), dried (Na2SO4) and concentrated to afford a brown oil that was chromatographed on a gm ISCO silica gel cartridge, eluting with a 0-50%EtOAc/Hexanes gradient. The pure fractions were concentrated to afford methyl 3-(3-amino-2-methoxyphenyl)-l-methyl-l//- pyrazole-5-carboxylate (89 mg, 0.337 mmol, 29.4 % yield) as a tan solid. LCMS m/z 262.2 (M+H)+; HPLC 1r 0.65 min (analytical HPLC Method A).
Step 2:To a solution of 4,6-dichloro-A-trideuteromethylpyridazine-3-carboxamide (mg, 0.344 mmol) and methyl 3-(3-amino-2-methoxyphenyl)-l-methyl-l//-pyrazole-5- carboxylate (90 mg, 0.344 mmol) in Tetrahydrofuran (3 mL) at rt was added dropwise over 5 minutes LiHMDS, IM (0.861 mL, 0.861 mmol). The resulting solution was stirred at rt for 30 minutes. The reaction mixture was quenched with 1 ml of saturated NH4C1 solution. The resulting mixture was partitioned between EtOAc (30 ml) and saturated NH4Cl solution (30 ml). The organic layer was washed with brine (30 ml), dried (Na2SO4) and concentrated to an amber oil that was chromatographed on a 12 gm ISCO silica gel cartridge, eluting with a 0-60%EtOAc/Hex gradient. The pure fractions were concentrated to afford methyl 3-(3-((6-chloro-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-l-methyl- 1/7- pyrazole-5-carboxylate (79 mg, 0.178 mmol, 51.8 % yield) as a tan solid. . LCMS m/z 434.2 (M+H)+; HPLC 1r 0.97 min (analytical HPLC Method A).
Step 3:A mixture of 3-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4- yl)amino)-2-methoxyphenyl)-l-methyl-l/7-pyrazole-5-carboxylate (0.141 g, 0.3mmol), Xantphos (0.038 g, 0.065 mmol), and cyclopropanecarboxamide (0.055 g, 0.6mmol) in dioxane (3 mL) was degassed by bubbling N2 through it for 5 minutes. Then C82CO3 (0.424 g, 1.300 mmol) and Pd2(dba)3 (0.030 g, 0.032 mmol) were added, the vessel was sealed, and the reaction was stirred at 130 °C for 45 minutes. The reaction was WO 2020/092196 PCT/US2019/058268 complete by LC-MS. The reaction was cooled to room temperature, then concentrated and loaded directly onto a 12g ISCO column for purification by flash chromatography, eluting with 0-15% MeOH in DCM to afford methyl 3-(3-((6- (cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2- methoxyphenyl)-l-methyl-l/7-pyrazole-5-carboxylate (99 mg, 0.203 mmol, 62.5 % yield) as a pale yellow solid. LCMS m/z 483.5 (M+H)+; HPLC /r 0.80 min (analytical HPLC Method A). 1HNMR (400MHz, DMSO-d6) 5 11.32 (s, 1H), 10.96 (s, 1H), 9.14 (s, 1H), 8.13 (s, 1H), 7.71 (dd, J=7.9, 1.6 Hz, 1H), 7.44 (dd, J=7.9, 1.5 Hz, 1H), 7.30 - 7.24 (m, 2H), 4.18 (s, 3H), 3.88 (s, 3H), 3.64 - 3.60 (m, 3H), 2.13 - 2.04 (m, 1H), 0.86 - 0.79 (m, 4H) Step 4: A mixture of methyl 3-(3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-l-methyl- 1/7- pyrazole-5-carboxylate (99 mg, 0.205 mmol) and lithium hydroxide monohydrate (10.mg, 0.246 mmol) in THF (2 mL) and Water (0.4 mL) was stirred at rt for 24 hr. The volatiles were removed in vacuo to afford 3-(3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-l-methyl- 1/7- pyrazole-5-carboxylic acid, lithium salt (96 mg, 0.192 mmol, 93 % yield) as a yellow solid. Used as is. LCMS m/z 469.4 (M+H)+; HPLC /r 0.70 min (analytical HPLC Method A).
Step 5:A mixture of 3-(3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-l-methyl- 1/7- pyrazole-5-carboxylic acid, lithium salt (10 mg, 0.021 mmol), thiomorpholine 1,1-dioxide (7.11 mg, 0.053 mmol), BOP (12.09 mg, 0.027 mmol) andEt3N (0.015 mL, 0.105 mmol) in DMF (0.2 mL) was agitated at rt for Ih. The reaction was complete by LC-MS, so the reaction was diluted to 1.5mL with methanol, then filtered and submitted for purification. The reaction afforded 6-(cyclopropanecarboxamido)-4-((3-(5-(l,l- dioxidothiomorpholine-4-carbonyl)-1 -methyl- 1H-pyrazol-3 -yl)-2- methoxyphenyl)amino)-A-trideuteromethylpyridazine-3-carboxamide (8.1 mg, 0.0 WO 2020/092196 PCT/US2019/058268 mmol, 60.5 % yield) LCMS m/z 586.4 (M+H)+; HPLC /r 0.68 min (analytical HPLC Method A).1H NMR (500MHz, DMSO-d6) 5 11.34 (s, 1H), 11.03 (s, 1H), 9.15 (s, 1H), 8.18 (s, 1H),7.70 (d, >רר Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.26 (t, J=1.7 Hz, 1H), 7.05 (s, 1H), 4.01(hr. s., 5H), 3.95 (s, 3H), 3.63 (s, 3H), 3.34 (hr. s., 2H), 2.12 - 2.04 (m, 2H), 0.91 - 0.(m, 4H) The Examples in Table 9 were prepared using a similar procedure used to prepareExample 455. Table 9 Ex.No.Structure MWObs. MS IonRTQC Method 456ם ם^ zx 512.6 513.2 1.35QC- ACN- AA-XB 457 ( NH O=< / rN- T । ^k^o ^^־NH O D /L ,N H HN N 495.6 496.2 1.49QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 458 D D oxTD NH N= n— M' )>— NH .° / ״ 1 ־ 0 = 2 4 V 525.6 526.4 1.43QC- ACN- AA-XB 459 o 0=( / rN~ T । Ox/O LI ^^NH 0 D D ,L ,N H HN N o° 537.6 538.4 1.35QC- ACN- AA-XB 460 Dx P 0o° y—NH ^OnH O'־ / 539.6 540.3 1.41QC- ACN- AA-XB 461 D J^O n D n'n^AJ / 0 HN'X^^ A nh° A l '7Q'0 H 539.6 540.3 1.36QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 462 h2n w T । 0 D 7,0 זז rYY^N^D N H , ؛■ L HN N 467.5 468.3 1.34QC- ACN- AA-XB 463 )=N 0 D D tC^Y^N^D ,N H HN N 467.5 468.2 1.28QC- ACN- AA-XB 464 D D ox y־D y—NH NH ,°- v HLz^ u u ^NH L/N'N^nA/ O H 553.6 554.3 1.69QC- ACN- AA-XB 465 h2n T । ^K/0 LI 0 D D /L ,N H HN N 4° 453.5 454.3 1.21QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 466 D D 0 A y—NH N= A— 4WLo °- NHVj Z n'n^^n^ 0 H 0 531.6 532.2 1.24QC- ACN- AA-XB 467 D D o y-D y—NH N,N=—NHP- y/n 0 H 511.6 512.2 0.92QC- ACN- TFA-XB 468 D P o y־D y—NH N= A— . N 4NH / 4v u yNH 0 H 495.6 496.4 1.16QC- ACN- AA-XB 469 D D Ox 4d y—NH N'N=—NHp— 4 v ——/ ? yNH o H 525.6 526.2 1.23QC- ACN- AA-XB 470 D D Ox 4D Y—NH n4 a— n' >—NHP 4V Hy-C' u yn V-y 0 H 520.6 521.4 1.21QC- ACN- AA-XB 471 / o Z I ל C v z 0 ^ / 4 j ל ؟ ° V 6 525.6 526.4 1.23QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 472 ox P o y־D y—NH xn^h ?־־ ^NH N'N^n4/° o' H 524.6 525.0 1.03QC- ACN- TFA-XB 473 Dx P o y־D >—NH xn^h ?־־؟ Vta (- ״ 4 y ^NH 4/ N'N^N4/0 o' H 524.6 525.4 1.09QC- ACN- TFA-XB 474 D D ox4d y—NH N= n — 4 y Pnh vj 4n'n'^n/yx o H OH 525.6 526.4 1.1QC- ACN- AA-XB 475 40 HN )=N /= w / 0 V—D Pn /° םס Nz Oh4| oh z4/nx4־x/ 597.7 598.3 1.63QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 476 OH o 0X / rN- XN T । ^k/° LI 0 D ld ןז ] rA/^N^D X ,N H HN N V^0 580.7 581.2 1.26QC- ACN- AA-XB 477 D P 0 y־D y—NH N=< n— J ))—NHP zH )—_)-n hVnho J520.6 521.2 1.4QC- ACN- AA-XB 478 OH d O=( / rN- XN T । LI ^"^NH O D D X ,N H HN N 4° 551.6 552.4 1.2QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 479ם ס o 535.6 536.2 1.57QC- ACN- AA-XB 480 d O=< /r N- On T ।LIO D D rbd^N'^'D /L ,N HKN N d،° 550.6 551.2 1.32QC- ACN- AA-XB 481 D Po y ־D y —NHN,NO—NH P" z1 ־ 0 (= 4U^Y״^/° 0 539.6 540.2 1.44QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 482 O=< / rN- T । 0 D D ,N H HN N V^0 521.6 522.2 1.51QC- ACN- AA-XB 483 0^ / rN- XN T । X,0 LI ^׳^NH O D D Jx ,N H HN N 495.6 496.4 1.32QC- ACN- AA-XB 484 L v L h X x < = > ، — ל ס 1 S •' 0 > v ° L ן ס ס o i 598.7 599.2 1.29QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 485 o Fn o ry O D AAw8 hn^n'n 555.6 556.3 1.46QC- ACN- AA-XB 486 0Y / F" ^n Y । ry ^^NH O D HN N V^° 494.6 495.3 1.21QC- ACN- AA-XB 487 HO / N Y । F/° ^Yh 0 D D NNkp Y ,N H HN N Y° 482.6 483.6 0.74 A WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 488 " H y o k o ־ ס ס 584.7 585.1 0.94QC- ACN- TFA-XB 489 oh Jx^-O^ F/^/J^NH 0 D ,N H HN N 500.6 501.2 1.57QC- ACN- AA-XB 490 y° 0 NH O=< / r״ X^N T । ^k/O LI ^^NH 0 D d ؛ > ־^ LtL^n ؛؛؛: f /، L H HN N ׳،° v 545.6 546.4 1.18QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 491 o hn"L^ aJCX j ׳ )=oH —N I N—A HN'X-q ־ 4 ■ 0 576.7 577.2 0.86QC- ACN- TFA-XB 492 /—NH o o=< / N H HN N A 536.6 537.2 0.83QC- ACN- TFA-XB 493 ^0 c O=< / ^nT । ^^nH 0 D ד,□ זז r/L ,N H HN N 578.6 579.4 1.02QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 494 oZ >° o N-' 0A / rN- T । A•-/0 0 D D X ,N H HN N A° 594.6 595.4 1.42QC- ACN- AA-XB 495 x <> - n3 x A،o ^ ז r F'^^NH 0 D D N H ״ X HN N A1 513.5 514.1 1.49QC- ACN- AA-XB 496 1 z 1 סx z ^ ס y V _ T 0 ״ V ״ 2 -2 ° 594.7 595.2 1.32QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 497 n'^ Jx/O^ r X F/^/^NH O D D ,N H HN N vY 568.6 569.3 1.44QC- ACN- AA-XB 498 ° E — y ° = < T / / = o o ' x ס ס 562.6 563.3 1.14QC- ACN- TFA-XB 499 0 __/ Yn % H H NxZ v Yx/°x r x 0 D 7,0 זז r Y ,N H HN N 583.6 584.3 1.72QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 500 HN—/ 0 ־^ N , N^J> F'^^NH 0 D D Jx ,N H HN N 499.5 500.4 1.33QC- ACN- AA-XB 501 o HN-S— N—(׳ n '% 0 Jx/O^ H 0 D 7,0 זז f YY^N^D /، ,N H HN N V^° 535.6 536.2 1.25QC- ACN- AA-XB 502 o / kN> ^N T । ^X/° ^^NH O D D N H HN N 614.7 615.2 1.39QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 503 o ؟° Y S N-/ —/ XO Y>/0 0 D D Y ,N H HN N 603.6 604.2 1.47QC- ACN- AA-XB 504 N D D נ d3< j Y HN >N Yh — °Y/N ־X—0 oYvnhnA590.7 591.4 0.93QC- ACN- TFA-XB 505 0 z__ Yn H x n^> /Y/° JM F'^^NH O D D YAn'^'d Y ,N H HN N Y° 527.6 528.3 1.62QC- ACN- AA-XB 506ם ס 1 o=<'־ ־ ^ z ' ־ ' / X ) = z s A ° v v z V _ ^ z ״ = 1 > 541.6 542.3 1.53QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 507 HO^_ 1JL F/x^NH 0 D D /L ,N H HN N Y° 569.6 570.1 1.31QC- ACN- TFA-XB 508 0 zo א / La j T F^^^NH O D D x، ,N H HN N vY 525.6 526.2 1.6QC- ACN- AA-XB 509 Z ^ Y —Z O Z > ' 0 Y ° ץI ס סס 597.7 598.3 1.27QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 510 D D °x /—NH N=/ 0 Ny P~ ° ^NH 511 O YY H vvw na Y^o^ If Y O D xk ,N H HN N Y° 629.7 630.4 1.9QC- ACN- TFA-XB 512 9/0 ^Yi^n'tX-O h/nA zn~N /— J7 -0 HNKEN HN~4 d-7( 0 D D 601.7 602.4 1.78QC- ACN- TFA-XB 513 D D °VYd /~NH N=/ 0 ° WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 514 D D °x >V /~NH N=/ 0N_—NH °~ 0 |VNH 515 -NV xnz/L/0^ F'Xs^<־NH 0 D D /L ,N H HN N V° 596.7 597.3 1.24QC- ACN- AA-XB 516 Vn >-nV nV LVnJNV F^V 0 D WNp ,N H HN N v° 622.7 623.5 1.25QC- ACN- AA-XB 517 ן Vn nV nV If T NH O D ^^־' / F 7 ,0 f jj d ־ > x ־ YYX'n , N H HN N ° v 582.7 583.3 1.11QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 518 o nY» If T F-^^NH O D ,N H HN N Y° 596.7 597.5 1.56QC- ACN- AA-XB 519 0 /_Z'° Yn NH NY N^ J^o^ Jf T O D JI JL YD (YY1Yd /L ,N H HN N Y° 568.6 569.3 1.31QC- ACN- AA-XB 520 D D °x Yd /~NH N=/ 0 NY^NV_v°~ ° >YNH 555.6 556.3 1.15QC- ACN- AA-XB 521 D D 9XYd /—NH N=/ 0 N^/ NY/°~ 0 oh ؟^ An ،^״ Vnh zYN'Nx h OH 541.6 542.3 1.2QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 522 ^0 0^ / n T । /k/0 ( T 0 D 7,0 ןז r N H HN N Y،° 551.6 552.3 1.44QC- ACN- AA-XB 523 D D Qx Y0 /—NH N=/ ° ° r0H Xn.،oh /؟ Vnh /M<1 V=/X M H X x—z N'nx541.6 542.3 0.92QC- ACN- TFA-XB 524 OH d d O=< / rN- T । ،״° x ( Y O D 7,0 ח r r<:Yr'N/^D /X ,N H HN N V^° 663.8 664.4 0.79QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 525 b- O=< /r N- T । ( TD D INKp /L ,N HHN N A 565.6 566.3 1.6QC- ACN- AA-XB 526 D D°x A0/—NHN=/1y /־a °— 0 ।VnH<1 1552.7 553.4 0.99QC- ACN- TFA-XB 527 D D/-NHN=/n^h o_ ° bNH WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 528 p NH / N T । x،,0 ( Y —^NH 0 D f Tf IdD /L ,N H HN N A 564.7 565.2 1.21QC- ACN- AA-XB 529 d 0^ / x^N Y । 0 D ^ANYD /L ,N H HN N 578.7 579.4 1.16QC- ACN- AA-XB 530 d O=< / rN- 604.7 605.4 1.19QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 531 o 0=( / rN' T । 0 D 7,0 זז f /U ,N H HN N 578.7 579.2 1.49QC- ACN- AA-XB 532 ox y—NH o / rN- ^n T । ( T O D f JI L.0 r^Tf'N'^D ,N H HN N V^° 550.6 551.3 1.19QC- ACN- AA-XB 533 D D ؟ /—NH N=/ O N^/ Ny P~ ° XN^ W " M H Y ׳ N'NX 578.7 579.2 1.24QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 534 / —N NH 0^ / r״ XN T । ^^NH 0 D 7,0 זז r YY^N^D ,N H HN N 592.7 593.4 1.26QC- ACN- AA-XB 535 ^NH 0=( / rN~ Yn I 1 ^^NH 0 D D r^Y^N^D /k- ,N H HN N A 509.6 510.3 1.64QC- ACN- AA-XB 536 D D /—NH NrV 0 °~ 0 | VnH< h538.6 539.3 1.21QC- ACN- AA-XB 537 D D D ^־ ؟ /-NH nY O- O ؟, O yJ^N Vnh Ha/n^n/ <1 ،/ N H 1 x/ —' N'nx 552.7 553.3 1.19QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 538 O=< / n ،׳, T । ( T 0 D D N H HN N 507.6 508.2 1.26QC- ACN- TFA-XB 539 c O=( / rN- cn T । /k/0 ( T ^^NH O D D x، ,N H HN N A 509.6 510.3 1.48QC- ACN- AA-XB 540 D D °x X־D }—NHN=< | 0n^>nh o_ ° <°Vnh<1 h569.6 570.2 1.23QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 541 / T । ( Y 0 D D N H HN N 632.8 633.4 1.22QC- ACN- AA-XB 542 D D DY .0 HN— ץ -n /=N 0 Tv>HnV'V H ،/ 549.6 550.3 0.61 A 543ם ם 538.6 539.3 1.39QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 544d ם A 566.6 567.0 1.61QC- ACN- AA-XB 545 HNYN'N T 1 H Y^n^d Fx^_MHo d d ך׳־׳רכ"'' NA -؟ N / □H 554.6 555.1 1.24QC- ACN- TFA-XB 546 OH Na> F^^^NH 0 D D Jx ,N H HN N A 526.6 527.2 1.23QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 547 OH LT F^^NH 0 D D /U ,N H HN N i^N L H HO^ 567.6 568.4 1.59QC- ACN- AA-XB 548 V/ /-N H X ^k^-O^, F'-'^-'^NH 0 D 7,0 ןז f ,N H HN N A 539.6 540.2 1.51QC- ACN- AA-XB 549 A HN. _N. , H TlfN'Y'D Fx^x/NH 0 D ° T T y^o'^ N. 7NA Z z —N or x 567.6 568.1 1.18QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 550 % / H J^O^ F^^^NH 0 D D ,N H HN N Y־N Ljl HO^ 580.6 581.3 1.54QC- ACN- AA-XB 551 V / /-N 0 D HN N /° 552.6 553.2 1.43QC- ACN- AA-XB 552 0 }—NH 0 ,NT J/O^ LT F/^/xNH O D HN^N^ A 588.6 589.1 1.25QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 553 H x ^L/O^ 0 D HN^N^ nAN-N 525.6 526.3 1.42QC- ACN- AA-XB 554 V / /~N nV r r F'^^NH 0 D D WNKp V ,N H HN N !v /° 553.6 554.1 1.51QC- ACN- AA-XB 555 V / H nV NV Vx/° LT F^^^NH O D D 1V>VN/kD V ,N H HN N 537.6 538.3 1.15QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Example 556 4-((3-(l-(2-acetamidoethyl)-lH-pyrazol-4-yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide Step 1: WO 2020/092196 PCT/US2019/058268 A solution of tert-butyl (2-(4-bromo-l/7-pyrazol-l-yl)ethyl)carbamate (0.18 g, 0.620 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (0.170 g, 0.682 mmol), and l,l'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.020 g, 0.031 mmol) was degassed by bubbling N2 through the solution for 5 minutes. Then 2M K3PO4 (aq) (0.931 mL, 1.861 mmol) was added and the mixture was stirred at 100 °C for Ih. LC-MS showed complete conversion to the desired product mass. The reaction mixture was cooled to room temperature, then diluted with EtOAc (75mL). This solution was then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography, eluting with 0-100% EtOAc in hexanes to afford tert-butyl (2-(4-(3- amino-2-methoxyphenyl)-l/7-pyrazol-l-yl)ethyl)carbamate (177 mg, 0.532 mmol, 86 % yield) in total, a yellow solid.LCMS m/z 333.2 (M+H)+; HPLC t K 0.68 min (analytical HPLC Method A).
Step 2:To a solution of 4,6-dichloro-A-trideuteromethylpyridazine-3-carboxamide (1mg, 0.586 mmol) and tert-butyl (2-(4-(3-amino-2-methoxyphenyl)-l/7-pyrazol-l- yl)ethyl)carbamate (177 mg, 0.532 mmol) in THE (5 mL) was added LiHMDS, IM in THF (2.130 mL, 2.130 mmol) and the reaction stirred at room temperature for a total of minutes. The crude reaction was quenched with sat. aqueous ammonium chloride, then diluted with EtOAc. The aqueous layer was washed 2x EtOAc, and the combined EtOAc layers were washed lx brine. This solution was thendried over sodium sulfate, then filtered and concentrated. The crude material was then loaded onto a 24g ISCO column for purification by flash chromatography. Eluted with 0-100% EtOAc in hexanes. The reaction afforded tert-butyl (2-(4-(3-((6-chloro-3-(trideuteromethylcarbamoyl) pyridazin-4-yl)amino)-2-methoxyphenyl)-l/7-pyrazol-l-yl)ethyl)carbamate (184 mg, 0.353 mmol, 66.4 % yield) as an off-white solid. LCMS m/z 505.4 (M+H)+; HPLC /r 0.min (analytical HPLC Method A); 1H NMR (400MHz, DMSO-d6) 5 11.10 (s, IH), 9.(s, IH), 8.16 (s, IH), 7.96 (s, IH), 7.52 (dd, 1=7.8, 1.2 Hz, IH), 7.37 (dd, 1=7.9, 1.4 Hz, IH), 7.25 -7.19 (m, IH), 7.17 (s, IH), 6.95 (t, 1=5.6 Hz, IH), 4.24 -4.15 (m, 2H), 3.60 (s, 3H), 3.39 - 3.34 (m, 2H), 1.38 - 1.33 (m, 9H) Step 3: WO 2020/092196 PCT/US2019/058268 A mixture of tert-butyl (2-(4-(3-((6-chl oro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-l/7-pyrazol-l- yl)ethyl)carbamate (182 mg, 0.360 mmol), Xantphos (41.7 mg, 0.072 mmol), and cyclopropanecarboxamide (92 mg, 1.081 mmol) in dioxane (3.5 mL) was degassed by bubbling N2 through it for 5 minutes. Then C82CO3 (470 mg, 1.442 mmol) and Pd2(dba)(33.0 mg, 0.036 mmol) were added, the vessel was sealed, and the reaction was stirred at 130 °C for Ih. The reaction was complete by LC-MS, so the crude material was concentrated diluted with EtOAc (75mL), then dried over sodium sulfate. The reaction mixture was filtered and concentrated, then loaded onto a 24g ISCO column for purification by flash chromaography, eluting with 0-15% MeOH in DCM to afford tert- butyl (2-(4-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin- 4-yl)amino)-2-methoxyphenyl)-lH-pyrazol-l-yl)ethyl)carbamate (155 mg, 0.266 mmol, 73.8 % yield). . LCMS m/z 554.6 (M+H)+; HPLC t K 0.81 min (analytical HPLC Method A)Step 4:A solution of tert-butyl (2-(4-(3-((6-(cyclopropanecarboxamido)-3- (trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-lH-pyrazol-l- yl)ethyl)carbamate (155 mg, 0.280 mmol) in DCM (3 mL) and HC1, 4M in 1,4-dioxane (0.700 mL, 2.80 mmol) was stirred at room temperature overnight. After stirring overnight, the reaction is complete. Concentrated to a yellow solid, used as-is in the next step. (4-((3-(l-(2-aminoethyl)-l//-pyrazol-4-yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)-A-trideuteromethylpyridazine-3-carboxamide (125 mg, 0.255 mmol, 91 % yield). LCMS m/z 454.3 (M+H)+; HPLC 1r 0.61 min (analytical HPLC Method A).
Step 5:To a solution of 4-((3-(l-(2-aminoethyl)-l/7-pyrazol-4-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-A-trideuteromethylpyridazine-3- carboxamide (12 mg, 0.026 mmol) in DMF (0.5 mL) and triethylamine (0.011 mL, 0.0mmol) was added acetic anhydride (3.74 pl, 0.040 mmol). The reaction was stirred at room temperature for 30 minutes, whereupon the reaction was complete by LC-MS. Quenched the excess acetic anhydride with methanol, then concentrated to a solid.
WO 2020/092196 PCT/US2019/058268 Redissolved in 2mL methanol, filtered and submitted for purification. The reaction afforded 4-((3-(l-(2-acetamidoethyl)-l//-pyrazol-4-yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)-7V-trideuteromethylpyridazine-3-carboxamide (7.5 mg, 0.0mmol, 56.6 % yield) LCMS m/z 496.2 (M+H)+; HPLC Zr 0.64 min (analytical HPLCMethod A); 1H NMR (500MHz, DMSO-d6) 5 11.33 (s, 1H), 10.97 (s, 1H), 9.15 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.02 (t, 1=5.4 Hz, 1H), 7.98 (s, 1H), 7.46 (d, 1=7.7 Hz, 1H), 7.29 (d, 1=7.4 Hz, 1H), 7.23 -7.17 (m, 1H), 4.22 (t, 1=6.1 Hz, 2H), 3.60 (s, 3H), 3.47 (q, 1=5.8 Hz, 1H), 2.12 - 2.04 (m, 2H), 1.80 (s, 3H), 0.88 - 0.77 (m, 4H) The Examples in Table 10 were prepared using a similar procedure used to prepare Example 556. Table 10 Ex.No.Structure MWObs. MS IonRTQC Method 557 h2n N-N & O D fך Ed N^D N H , ؛؛. J HN N v 453.5 454.3 0.98QC- ACN- AA-XB 558 T o z - ^ / / A J » ؟ ° 1 L 0 " Y l x z ל — 511.6 512.2 1.1QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 559 D D 0. y—NH yN״ 0 H 520.6 521.3 1.25QC- ACN- AA-XB 560 D D 0 ^־D —NH N'N=yNH /°' r™ •MF 531.6 532.2 1.24QC- ACN- AA-XB 561 D D ox ^־D ——NH !?s-™ P" A)"V-C" 0 1/ o H 553.6 554.3 1.6QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 Example 563 Ex.No.Structure MWObs. MS IonRTQC Method 562 D D^־DNH 4 H )—_F9 1h K/N-AsA°-H525.6 526.4 1.23QC- ACN- AA-XB 4-((3-(l-(2-acetamidoethyl)-lH-pyrazol-4-yl)-2-methoxyphenyl)amino)-6- (cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide The Examples in Table 11 were prepared using a similar procedure used to prepare Example 563. Table 11 WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 564 o N-' O=( & 0 D f IT 7,0 rA/W N H HN N ،-N 580.6 581.2 1.71QC- ACN-AA- XB 565 D D 0 VD y—NH N= n— N / MV" dVMs^ '—' 0 568.6 569.0 1.57QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 566 D D 0 y—NH N= n— N' )>— NH ,° V■ - ° o 528.6 529.3 1.5QC- ACN-AA- XB 567 D D 0 y־D y—NH /-s N-N 1 H Q -nh o 567.6 568.1 1.27QC- ACN- TFA-XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 568 o 0=( O D 7,0 ח Y /L ,N H HN N ku F 581.6 582.2 1.82QC- ACN-AA- XB 569 D D ox y-° y—NH NH /O— V ° o 527.6 528.1 1.24QC- ACN- TFA-XB 570 D D oxTD y—NH N= n— N׳ Vnfi 0 xa_cyr O 568.6 569.2 1.71QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 571 D D ox ^NH N= n— U-GKo w 0 HO' 595.7 596.2 1.61QC- ACN-AA- XB 572 o N-' 0=( FSX & O D [ ך l.d r^Sr^N^D xk ,N H HN N /0 580.6 581.2 1.66QC- ACN-AA- XB 573 o x z V o rx I 1 H A ؟ a j L x x X A u. Q 1 I ° r ־ o 1 x 612.7 613.3 1.55QC- ACN-AA- XB WO 2020/092196 PCT/US2019/058268 Ex.No.Structure MWObs. MS IonRTQC Method 574 D Po y ־Dy —NH<1 >־Gn ״ y-NH —''o'° v 0 545.6 546.1 1.66QC- ACN-AA- XB 575 D Dy ־D>—NH /-sX N-N V tVTl N / xo-? xVnh n<:kyn^^o/ 585.6 586.1 1.27QC- ACN- TFA-XB Example 576 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(3-(morpholinomethyl)-l,2,4- oxadiazol-5-yl)phenyl)amino)nicotinamide WO 2020/092196 PCT/US2019/058268 Step-1 Step-2 Step-5 Step-3 Step-6 Step-4 Step 1:A mixture of tert-butyl 2-methoxy-3 -nitrobenzoate (200 mg, 0.790 mmol) and % Palladium on carbon (42.0 mg, 0.039 mmol) in ethyl acetate (8 ml) was stirred under an atmosphere of hydrogen at rt for 16 hr. Filtration through a 0.45 micron nylon filter WO 2020/092196 PCT/US2019/058268 and concentration of the filtrate afforded tert-butyl 3-amino-2-m ethoxybenzoate (165 mg, 0.739 mmol, 94 % yield) as a yellow oil. HPLC /r 1.43 min (analytical HPLC Method A) 1H NMR (400MHz, CHLOROFORM-d) 5 7.11 (dd, 1=7.7, 1.8 Hz, 1H), 6.96 - 6.89 (m, 1H), 6.88 - 6.83 (m, 1H), 3.84 (s, 3H), 1.60 (s, 9H).
Step 2:To a heterogeneous, colorless solution of 4,6-dichloronicotinic acid (1 g, 5.mmol) in Dichloromethane (35 mL) under nitrogen was added oxalyl dichloride (0.5mL, 6.77 mmol), followed by DMF (0.403 mL, 5.21 mmol); efferescence ensued. LCMS after 2 h of mostly homogeneous solution showed completion of reaction (quenched with ethanol, see ethyl ester M+H 219.9). The solution was concentrated in vacuo; DCE (mL) was added, and the solution was concentrated in vacuo. This was repeated twice to give crude 4,6-dichloronicotinoyl chloride. Poured 50mL 28% ammonium hydroxide into a separatory funnel, extracted 3x 15mL DCM. Dried the combined DCM layers over sodium sulfate, then filtered and used this ammonia solution as is in the reaction. This solution was added to a homogeneous yellow solution of 4,6-dichloronicotinoyl chloride (1.1 g, 5.23 mmol) in 5mL DCM at 0 °C and TEA (2.186 mL, 15.68 mmol). After minutes, the reaction was complete by LC-MS. Diluted with di chloroethane (100 mL) and washed with 1 N aqueous HC1. The layers were separated, and the aqueous layer was extracted with di chloroethane (2x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was taken up in DCM, then purified by flash chromatography using an 40g silica gel column eluting with 0-100% ethyl acetate in hexanes. Appropriate fractions were collected and concentrated in vacuo to give 4,6-dichloronicotinamide (0.787 g, 3.91 mmol, 74.9 % yield). LCMS m/z 190.(M+H)+; HPLC fe 0.54 min (analytical HPLC Method A). 1HNMR (400MHz, DMSO- d 6) 5 8.51 - 8.49 (m, 1H), 8.11 (br. s., 1H), 7.91 - 7.87 (m, 2H) Step 3:To a solution of 4,6-dichloronicotinamide (192 mg, 1.008 mmol) and tert-butyl 3- amino-2-methoxybenzoate (225 mg, 1.008 mmol) in Tetrahydrofuran (6 mL) at rt was added dropwise over 1 minute LiHMDS, IM (2.52 mL, 2.52 mmol). The resulting solution was stirred at room temperature for 1 hr. The reaction mixture was quenched WO 2020/092196 PCT/US2019/058268 with 1ml of saturated aqueous ammonium chloride solution. The resulting mixture was partitioned between EtOAc (30 ml) and saturated NH4C1 solution (30 ml). The organic layer was washed with brine (30 ml), dried (Na2SO4) and concentrated to an amber oil that was chromatographed on a 12 g silica gel cartridge, eluting with a 0-100% ethyl acetate in hexanes gradient. The pure fractions were concentrated to afford tert-butyl 3- ((5-carbamoyl-2-chloropyridin-4-yl)amino)-2-methoxybenzoate (106 mg, 0.267 mmol, 26.4 % yield) as a light yellow solid. LCMS m/z 378.2 (M+H)+; HPLC Zr 0.91 min (analytical HPLC Method A). 1HNMR (400MHz, DMSO-d6) 5 11.09 (s, 1H), 9.37 (s, 1H), 7.72 (dd, 1=7.9, 1.3 Hz, 1H), 7.49 (dd, 1=7.8, 1.4 Hz, 1H), 7.27 (t, 1=7.9 Hz, 1H), 7.19 (s, 1H), 3.74 (s, 3H), 1.56 (s, 9H).
Step 4:A mixture of tert-butyl 3-((5-carbamoyl-2-chloropyridin-4-yl)amino)-2- methoxybenzoate (22 mg, 0.058 mmol), cyclopropanecarboxamide (49.6 mg, 0.5mmol), Pd2(dba)3, Chloroform adduct (6.02 mg, 5.82 umol), Xantphos (6.74 mg, 0.0mmol) and C82CO3 (76 mg, 0.233 mmol) in Dioxane (1.5 mL) was degassed by bubbling N2 through the mixture for 5 minutes. The reaction vessel was sealed and heated to 1°C overnight. After cooling to rt, the reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (30 ml) and the combined organics were dried (Na2SO4) and concentrated to afford a yellow oil that was chromatographed on a 12 g silica gel cartridge, eluting with a 0-100% ethyl acetate in hexanes gradient. The pure fractions were concentrated to afford tert-butyl 3-((5- carbamoyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoate (mg, 0.028 mmol, 48.3 % yield) as a yellow solid. LCMS m/z 427.3 (M+H)+; HPLC Zr 0.75 min (analytical HPLC Method A).
Step 5:A mixture of tert-butyl 3-((5-carbamoyl-2-(cyclopropanecarboxamido)pyridin-4- yl)amino)-2-methoxybenzoate (35 mg, 0.082 mmol) and HC1, 4N in dioxane (0.205 mL, 0.821 mmol) in DCM (1.5 mL) was stirred at rt for 8 hr. The reaction mixture was allowed to stand at rt over the weekend in the freezer. The volatiles were removed in vacuo and the residue was dried to afford 3-((5-carbamoyl-2- WO 2020/092196 PCT/US2019/058268 (cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoic acid, HC1 (36 mg, 0.080 mmol, 97 % yield) as a yellow solid.
Step 6:A mixture of 3-((5-carbamoyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)- 2-methoxybenzoic acid, HC1 (35 mg, 0.089 mmol),(Z)-A'-hydroxy-2- morpholinoacetimidamide (17.00 mg, 0.107 mmol), BOP (59.0 mg, 0.133 mmol) and Et3N (0.037 mL, 0.267 mmol) in DMF (1 mL) was stirred at room temperature for 1.5 hr. The reaction mixture was partitioned between EtOAc (20 ml) and saturated sodium bicarbonate solution (20 ml). The organic layer was washed with water (2 x 20 ml) and brine (20 ml). After drying (Na2SO4) and filtration the organic layer was concentrated to afford (Z)-4-((3-((((l-amino-2-morpholinoethylidene)amino)oxy)carbonyl)-2- methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide (40 mg, 0.070 mmol, % yield) as a light yellow oil. Used as is in the next step. ). LCMS m/z 512.4 (M+H)+; HPLC Zr 0.51 min (analytical HPLC Method A).
Step 7:A mixture of (Z)-4-((3-((((l-amino-2-morpholinoethylidene)amino) oxy)carbonyl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide (mg, 0.070 mmol) and TBAF, IM in THE (0.106 mL, 0.106 mmol) in acetonitrile (1 mL) was stirred at rt overnight. After stirring overnight, the reaction is complete. The reaction mixture was concentrated to an oil then redissolved in 1.5mL DMF, filtered and submitted for purification. The reaction afforded 6-(cyclopropanecarboxamido)-4-((2- methoxy-3-(3-(morpholinomethyl)-l,2,4-oxadiazol-5-yl)phenyl)amino)nicotinamide (12.4 mg, 0.024 mmol, 34.6 % yield) LCMS m/z 494.4 (M+H)+; HPLC fe 0.53 min (analytical HPLC Method A). 1HNMR (500MHz, DMSO-d6) 5 11.05 (s, 2H), 10.80 (s, 1H), 8.64 (s, 1H), 8.21 (br. s., 1H), 8.04 (s, 1H), 7.76 (d, 1=8.1 Hz, 2H), 7.55 (br. s, 1H), 7.40 (t, 1=7.9 Hz, 1H), 3.77 (s, 3H), 3.19 - 3.13 (m, 2H), 2.02 - 1.95 (m, 1H), 1.57 (br. s., 2H), 1.36 - 1.27 (m, 2H), 0.93 (t, 1=7.4 Hz, 3H), 0.79 (d, 1=6.1 Hz, 4H) The Examples in Table 12 were prepared using a similar procedure used to prepare Example 576.
WO 2020/092196 PCT/US2019/058268 Table 12 Ex.No.Structure MWObs. MS IonRTQC Method 577 o _ zz ■ Z . / = / 1־ T.Z /O RsA 570.6 571.2 1.26QC- ACN- AA-XB 578 0 --- .VN N^o O-/ H H 0552.6 553.0 1.37QC- ACN- AA-XB Example 579 N-(4-((2-methoxy-3-(3-(morpholinomethyl)-l,2,4-oxadiazol-5- yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide WO 2020/092196 PCT/US2019/058268 Step 1:To a solution of 4-bromopyridin-2-amine (300 mg, 1.734 mmol) and triethylamine (0.725 mL, 5.20 mmol) in DCM (15 mL) at 0 °C in an ice bath was added dropwise cyclopropanecarbonyl chloride (0.189 mL, 2.081 mmol). This solution was allowed to warm to room temperature after addition was complete. After 1 hour, the reaction is complete. Quenched with saturated aq. sodium bicarbonate, then extracted 3x 50mL DCM. Dried over sodium sulfate, then filtered and concentrated. The reaction afforded N- (4-bromopyridin-2-yl)cyclopropanecarboxamide (401 mg, 1.580 mmol, 91 % yield) as a crystalline off-white solid. Carried on directly to the next step as-is. HPLC /r 0.87 min (analytical HPLC Method A).
Step 2:A mixture of A-(4-bromopyridin-2-yl)cyclopropanecarboxamide (100 mg, 0.4mmol), Xantphos (48.0 mg, 0.083 mmol), and tert-butyl 3-amino-2-methoxybenzoate (185 mg, 0.830 mmol) in dioxane (3.5 mL) was degassed by bubbling N2 through it for minutes. Then C82CO3 (541 mg, 1.659 mmol) and Pd2(dba)3 (38.0 mg, 0.041 mmol) were added, the vessel was sealed, and the reaction was stirred at 130 °C for 45 minutes. The reaction was complete by LC-MS. The reaction was cooled to room temperature, and then concentrated, then diluted with DCM and loaded directly onto a 40g silica gel column. Eluted with 0-15% MeOH in DCM. The reaction afforded tert-butyl 3-((2- (cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoate (100 mg, 0.248 WO 2020/092196 PCT/US2019/058268 mmol, 59.7 % yield). ) LCMS m/z 384.2 (M+H)+; HPLC /r 0.77 min (analytical HPLC Method A).
Step 3:A mixture of tert-butyl 3-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2- methoxybenzoate (108 mg, 0.282 mmol) and HC1, 4N in dioxane (0.704 mL, 2.82 mmol) in DCM (3 mL) was stirred at rt for 8 hr. The reaction mixture was allowed to stir at rt. The volatiles were removed in vacuo and the residue was dried to afford 3-((2- (cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoic acid, HC1 (100 mg, 0.261 mmol, 93 % yield) as a yellow solid. ) LCMS m/z 328.2 (M+H)+; HPLC /r 0.min (analytical HPLC Method A).
Step 4:A mixture of 3-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2- methoxybenzoic acid, HC1 (40 mg, 0.114 mmol),(Z)-A'-hydroxy-2- morpholinoacetimidamide (21.81 mg, 0.137 mmol), BOP (76 mg, 0.171 mmol) and Et3N (0.048 mL, 0.343 mmol) in DMF (1 mL) was stirred at rt for 1.5 hr. The reaction mixture was partitioned between EtOAc (20 ml) and saturated sodium bicarbonate solution (ml). The organic layer was washed with water (2 x 20 ml) and brine (20 ml). After drying (Na2SO4) and filtration the organic layer was concentrated to afford (Z)-A-(4-((3- ((((l-amino-2-morpholinoethylidene)amino)oxy)carbonyl)-2- methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide (44 mg, 0.094 mmol, % yield) as a light yellow oil. Used as is. ) LCMS m/z 469.2 (M+H)+; HPLC fa 0.50 min (analytical HPLC Method A).
Step 5:A mixture of (Z)-A-(4-((3-((((l-amino-2-morpholinoethylidene)amino)oxy) carbonyl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide (44 mg, 0.0mmol) and TBAF, IM in THE (0.141 mL, 0.141 mmol) in Acetonitrile (1 mL) was stirred at rt over the weekend.The reaction was incomplete, so another 300uL of the TBAF solution was added, and the reaction allowed to stir another night at room temperature.the reaction is now complete by LC-MS. The reaction mixture was partitioned between WO 2020/092196 PCT/US2019/058268 EtOAc (30 ml) and brine. After drying (Na2SO4) and filtration the organic layer was concentrated to afford a yellow oil. This was dissolved in 2mL methanol, then filtered and submitted for purification. The reaction afforded A-(4-((2-methoxy-3-(3- (morpholinomethyl)- 1,2,4-oxadiazol-5-yl)phenyl)amino)pyri din-2-yl)cyclopropanecarboxamide (22.2 mg, 0.049 mmol, 51.9 % yield). ) LCMS m/z 451.(M+H)+; HPLC fe 0.51 min (analytical HPLC Method A). 1HNMR (500 MHz, DMSO- d 6) 5 10.66 - 10.37 (m, 1H), 8.63 (s, 1H), 7.95 (br d, J=5.4 Hz, 1H), 7.78 - 7.74 (m, 2H), 7.63 (br d, J=1.7 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 6.60 (br d, J=AA Hz, 1H), 3.76 (s, 2H), 3.71 (s, 3H), 3.63 - 3.60 (m, 2H), 3.19 - 3.14 (m, 2H), 2.60 - 2.53 (m, 4H), 2.00 - 1.95 (m, 1H), 1.57 (brs, 2H), 1.35 - 1.28 (m, 2H) The Examples in Table 13 were prepared using a similar procedure used to prepare Example 579. Table 13 Ex.No.Structure MWObs. MS IonRTQC Method 580 0 N— '—N N-0 O'--' H HA ן ן // _ ،.N 0 491.6 492.3 1.26QC- ACN- AA-XB 581< ^= °I Z .p y A 527.6 528.2 1.32QC- ACN- AA-XB WO 2020/092196 PCT/US2019/058268 BIOLOGICAL ASSAYSThe following assay is used to show the activity for compounds of the invention.
IFNa-Induced STAT Phosphorylation in Human Whole BloodAfter an hour long incubation with compound, human whole blood (drawn with either EDTA or ACD-A as anti-coagulant) was stimulated with 1000 U/mL recombinant human IFNa A/D (R&D Systems 11200-2) for 15 min. The stimulation was stopped by adding Fix/Lyse buffer (BD 558049). Cells were stained with a CD3 FITC antibody (BD 555916), washed, and permeabilized on ice using Perm III buffer (BD 558050). Cellswere then stained with an Alexa-Fluor 647 pSTAT5 (p¥694) antibody (BD 612599) for min prior to analysis on the FACS Canto II. The amount of pSTAT5 expression was quantitated by median fluorescence intensity after gating on the CD3 positive population.
IFNa-Induced STAT Phosphorylation in Human Whole Blood Inhibition DataND - no data availableTABLE 14 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)2.800.650.980.663.300.11ד 0.0240.0210.0160.0040.0210.0110.0240.050.03 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)0.560.49ND0.251.500.022ND0.060.240.433.902.010.210.131.380.380.08ND1.010.120.030.0180.030.0230.0120.060.230.170.0090.160.140.140.0250.050.070.160.090.21ND WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)0.040.120.0090.0110.0130.0230.060.080.030.110.0160.030.060.0230.030.0140.0250.080.280.170.030.03דד 0.040.070.160.110.180.070.110.130.240.300.460.230.030.060.050.030.05 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)0.0110.0210.0150.030.0230.04100 0.06105 1.83107 0.82109 >10.00115 3.49116 4.97118 3.80119 >10.00120 0.15121 >10.00122 >10.00123 >10.00124 0.21125 0.06126 0.63127 0.26128 0.03129 0.26130 0.49131 0.74132 0.30133 0.10134 0.11135 2.01136 1.13137 2.64138 0.18139 0.41140 0.33141 0.24142 5.31143 0.32144 1.00 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)145 0.27146 0.21147 1.72148 1.82149 1.95150 >10.00151 1.55152 1.31153 >10.00154 1.11155 0.78156 0.63157 >10.00158 0.40159 1.08160 1.79161 9.42162 2.73163 1.76164 0.20165 0.53166 ND167 2.42168 0.23169 0.11170 0.57171 0.69172 1.44173 0.30174 0.56175 0.66176 0.45177 1.03178 0.55179 0.29180 0.20181 0.63182 2.01183 1.68 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)184 0.13185 >10.00186 0.79187 1.13188 1.27189 0.10190 2.36191 0.41192 0.87193 7.36194 0.16195 0.72196 1.18197 6.20198 1.65199 1.08200 0.76201 0.29202 1.80203 0.46204 0.14205 0.85206 >10.00207 0.48208 1.27209 1.37210 0.22211 0.44212 0.32213 4.44214 0.39215 0.15216 0.32217 0.18218 0.39219 5.24220 0.20221 0.16222 1.48 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)223 0.69224 0.88225 0.35226 1.16227 0.62228 0.18229 >10.00230 0.51231 1.75232 6.51233 0.10234 0.30235 0.05236 >10.00237 0.07238 0.08239 0.05240 0.18241 0.62242 0.021243 0.09244 0.12245 0.11246 0.03247 0.10248 2.24250 0.64251 ND252 3.27253 0.30254 5.43255 0.62256 0.13257 0.23258 0.13259 >10.00260 0.54261 0.68262 2.69 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)263 0.83264 1.55265 0.53266 2.53267 0.15268 0.10269 0.04270 0.10271 0.09272 0.16273 0.07274 0.05275 0.15276 0.69277 0.24278 ND279 0.47280 ND281 >10.00282 0.18283 0.36284 >10.00285 ND286 ND287 1.26288 0.09289 0.15290 0.10291 0.11292 0.16293 0.03294 0.07295 0.06296 >10.00297 0.03298 >10.00299 0.014300 0.33301 0.03 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)302 0.11303 0.10304 0.13305 0.22306 0.44307 0.03309 >10.00310 >10.00311 0.20312 0.07313 0.07314 0.26315 0.022316 0.33317 0.03318 0.08319 0.03320 0.05321 0.03322 0.08324 0.06325 0.11326 0.03327 0.15328 0.16329 0.05330 0.07331 0.56332 0.04334 0.05335 0.05336 0.26337 0.07338 0.42339 0.04340 0.10341 0.11342 0.08343 0.022 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)344 0.03345 0.18346 0.09347 0.013348 ND349 0.07350 0.04351 0.06352 0.07353 0.17354 0.08355 0.38356 0.08357 0.88358 0.21359 0.34360 0.27361 0.19362 0.27363 0.24364 0.44365 0.32366 0.51367 0.06368 0.35369 0.05370 0.16371 0.31372 0.15377 1.41379 0.56380 ND381 0.13382 0.10383 0.03384 0.04385 0.18386 0.49387 0.27 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)388 >10.00389 0.57390 0.24391 0.82392 0.023393 0.18394 0.42395 0.08396 0.12397 0.04398 ND399 0.18400 0.03401 0.18402 0.04403 0.19404 0.11405 0.09406 0.18407 0.16408 0.11409 >10.00410 0.26411 1.80412 4.62413 0.17414 0.31415 0.04416 0.46418 0.13419 0.20420 0.22421 0.29422 0.59423 ND424 0.20425 0.67426 0.03427 0.09 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)428 2.63429 0.19430 >10.00431 >10.00432 0.30433 0.16434 0.16435 0.26436 0.30437 2.41438 2.89439 0.44440 1.16441 0.29442 0.08443 0.27444 2.13445 0.15446 0.27447 0.16448 0.14449 ND450 0.20451 0.06452 0.15453 0.06454 0.19455 0.56456 0.06457 0.77458 1.21459 0.08461 0.22462 4.45463 0.80464 1.11465 0.13466 0.42467 0.20 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)468 0.27469 0.20470 0.34471 1.59472 0.29473 >10.00474 3.56475 2.32476 0.06477 1.10478 0.15479 0.11480 0.07481 0.39482 0.15483 0.06484 0.10485 0.13486 0.06487 0.20488 0.53489 0.29491 0.26492 0.15493 0.04494 0.25495 0.06496 0.25497 0.11499 0.18500 0.37501 1.13502 0.15503 0.86504 >10.00505 0.18506 0.25507 0.11508 ND WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)509 0.17510 0.46511 0.32512 2.56513 >10.00514 0.87515 0.29516 0.17517 0.35518 0.15519 0.57520 0.77521 2.41522 0.19523 1.68524 3.40525 0.24526 0.52527 0.95528 0.84529 0.20530 0.20531 0.06532 0.47533 0.53534 0.47535 1.50536 0.65537 0.70538 0.39539 0.12540 0.46541 1.39542 0.89543 ND544 ND545 0.22546 0.11547 0.40 WO 2020/092196 PCT/US2019/058268 Ex. No.Human WB IFNa-Induced Stat Phosph. (IC50, pM)548 0.17549 ND550 0.24551 0.05552 3.60553 0.12554 ND555 0.04556 1.07557 0.72558 1.30559 0.83560 2.21561 4.36562 0.65563 3.12564 >10.00565 0.25566 0.68567 0.70568 ND569 0.59570 0.93571 1.76573 2.00574 0.70575 ND576 0.013577 0.019578 4.34581 ND

Claims (5)

282840/2 - 279 - CLAIMS
1. A compound which is6‐cyclopropaneamido‐4‐{[2‐methoxy‐3‐(5‐{1‐[(2‐methoxyethyl)carbamoyl]propyl}‐1,2,4‐oxadiazol‐3‐yl)phenyl]amino}‐N‐(2H3)methylpyridazine‐3‐carboxamide,6‐cyclopropaneamido‐4‐[(2‐methoxy‐3‐{5‐[1‐(morpholin‐4‐yl)‐1‐oxopentan‐2‐yl]‐1,2,4‐oxadiazol‐3‐yl}phenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide,6‐cyclopropaneamido‐4‐{[2‐methoxy‐3‐(5‐{1‐[(2‐methoxyethyl)carbamoyl]butyl}‐1,2,4‐oxadiazol‐3‐yl)phenyl]amino}‐N‐(2H3)methylpyridazine‐3‐carboxamide,tert‐butyl N‐[(1R,2R)‐2‐(tert‐butoxy)‐1‐{5‐[3‐({6‐cyclopropaneamido‐3‐[(2H3)methylcarbamoyl]pyridazin‐4‐yl}amino)‐2‐methoxyphenyl]‐1,2,4‐oxadiazol‐3‐yl}propyl]carbamate,6‐cyclopropaneamido‐4‐[(3‐{3‐[(1R,2R)‐1‐acetamido‐2‐hydroxypropyl]‐1,2,4‐oxadiazol‐5‐yl}‐2‐methoxyphenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide,methyl N‐[(1R,2R)‐1‐{5‐[3‐({6‐cyclopropaneamido‐3‐[(2H3)methylcarbamoyl]pyridazin‐4‐yl}amino)‐2‐methoxyphenyl]‐1,2,4‐oxadiazol‐3‐yl}‐2‐hydroxypropyl]carbamate,6‐cyclopropaneamido‐4‐[(3‐{3‐[(1R,2R)‐2‐hydroxy‐1‐propanamidopropyl]‐1,2,4‐oxadiazol‐5‐yl}‐2‐methoxyphenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide,tert‐butyl N‐[(1R)‐2‐(tert‐butoxy)‐1‐{5‐[3‐({6‐cyclopropaneamido‐3‐[(2H3)methylcarbamoyl]pyridazin‐4‐yl}amino)‐2‐methoxyphenyl]‐1,2,4‐oxadiazol‐3‐yl}ethyl]carbamate,6‐cyclopropaneamido‐4‐[(3‐{3‐[(1R)‐2‐hydroxy‐1‐propanamidoethyl]‐1,2,4‐oxadiazol‐5‐yl}‐2‐methoxyphenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide,6‐cyclopropaneamido‐4‐[(3‐{3‐[(1R)‐1‐acetamido‐2‐hydroxyethyl]‐1,2,4‐oxadiazol‐5‐yl}‐2‐methoxyphenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide,(2R)‐2‐{5‐[3‐({6‐cyclopropaneamido‐3‐[(2H3)methylcarbamoyl]pyridazin‐4‐yl}amino)‐2‐methoxyphenyl]‐1,2,4‐oxadiazol‐3‐yl}‐2‐acetamidoethyl acetate,6‐cyclopropaneamido‐4‐[(3‐{3‐[(1R)‐2‐hydroxy‐1‐(2‐methoxyacetamido)ethyl]‐1,2,4‐oxadiazol‐5‐yl}‐2‐methoxyphenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide, 282840/2 - 280 - 6‐cyclopropaneamido‐4‐[(3‐{3‐[(1S,2S)‐1‐acetamido‐2‐hydroxypropyl]‐1,2,4‐oxadiazol‐5‐yl}‐2‐methoxyphenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide,6‐cyclopropaneamido‐4‐[(3‐{3‐[(1S,2S)‐2‐hydroxy‐1‐(2‐methoxyacetamido)propyl]‐1,2,4‐oxadiazol‐5‐yl}‐2‐methoxyphenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide,tert‐butyl N‐[(1S,2S)‐2‐(tert‐butoxy)‐1‐{5‐[3‐({6‐cyclopropaneamido‐3‐[(2H3)methylcarbamoyl]pyridazin‐4‐yl}amino)‐2‐methoxyphenyl]‐1,2,4‐oxadiazol‐3‐yl}propyl]carbamate,6‐cyclopropaneamido‐4‐[(3‐{3‐[(1S,2S)‐2‐hydroxy‐1‐propanamidopropyl]‐1,2,4‐oxadiazol‐5‐yl}‐2‐methoxyphenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide,tert‐butyl N‐[(1S)‐2‐(tert‐butoxy)‐1‐{5‐[3‐({6‐cyclopropaneamido‐3‐[(2H3)methylcarbamoyl]pyridazin‐4‐yl}amino)‐2‐methoxyphenyl]‐1,2,4‐oxadiazol‐3‐yl}ethyl]carbamate, or6‐cyclopropaneamido‐4‐[(3‐{3‐[(1S)‐1‐acetamido‐2‐hydroxyethyl]‐1,2,4‐oxadiazol‐5‐yl}‐2‐methoxyphenyl)amino]‐N‐(2H3)methylpyridazine‐3‐carboxamide, or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 and a pharmaceutically acceptable carrier or diluent.
3. A compound according to anyone of claims 1 or a stereoisomer or pharmaceutically acceptable salt thereof for use in therapy.
4. A compound according to anyone of claims 1 or a stereoisomer or pharmaceutically acceptable salt thereof for use in treating an inflammatory or autoimmune disease.
5. The compound or stereoisomer or pharmaceutically acceptable salt thereof for use according to claim 4 wherein the inflammatory or autoimmune disease is multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn’s Disease, Sjögren’s syndrome or scleroderma. 282840/2 - 281 - Dr. Shlomo Cohen & Co. Law Offices B. S. R Tower 3Kineret StreetBnei Brak 5126237Tel. 03 - 527 1919
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